4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines

ABSTRACT

This disclosure describes novel 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines having antiasthmatic activity.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of our copending application Ser. No.927,572, filed Nov. 6, 1986, now U.S. Pat. No. 4,788,195, which is acontinuation-in-part of our abandoned application Ser. No. 817,951,filed Jan. 13, 1986, abandoned.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new organic compounds and, more particularly,is concerned with novel4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines havinganti-asthmatic activity which may be represented by the followingstructural formula: ##STR1## wherein R₁ is hydrogen, alkyl(C₁ -C₃),--COCO₂ C₂ H₅ or N,N-dimethylaminoethyl; R₂ is mono- or poly-substitutedphenyl wherein the substituents are alkyl(C₁ -C₆), alkoxy(C₁ -C₃),chloro, bromo, iodo, trifluoromethyl, hydroxy, phenyl, amino,monoalkyl-(C₁ -C₃)amino, dialkyl(C₁ -C₃)amino, alkyl(C₁ -C₃)keto,propenyloxy, carboxyl, oxyacetic acid, oxyacetic acid ethyl ester,sulfamilamido, N,N-dialkyl(C₁ -C₃)sulfamilamido, N-methylpiperazinyl,piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl,1-naphthyl, cyclopentyl, 3,4-dimethylbenzyl or moieties of the formula:##STR2## wherein R is alkyl(C₁ -C₃), X is oxygen (--O--) or sulfur(--S--), m is 1-3, n is 2 or 3, R₆ is hydrogen, alkyl(C₁ -C₃), alkoxy(C₁ -C₃), chloro, bromo, iodo or trifluoromethyl, R₇ is 1H-imidazol-1-ylor morpholino and R₈ is alkyl(C₁ -C₃), phenyl or monosubstituted phenylwherein the substituents are alkyl(C₁ -C₃), halogen or trifluoromethyl;R₃ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl,4-methyl-3-pyridinyl, 2-furanyl, 5-methyl-2-furanyl,2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl,2-pheno-thiazinyl, 4-pyrazinyl, 2-benzofuranyl, 2-(pyridine-N-oxide),3-(pyridine-N-oxide), 4-(pyridine-N-oxide), 1H-indol-2-yl,1H-indol-3-yl, 1-methyl-1H-pyrrol-2-yl, 4-quinolinyl, 4-pyridinyl methyliodide, dimethylaminophenyl or N-acetyl-N-methylaminophenyl; R₄ ishydrogen or alkyl(C₁ -C₃); and R₅ is hydrogen or alkyl(C₁ -C₃); and thepharmacologically acceptable acid-addition salts thereof.

The present invention also includes novel compositions of mattercontaining the above-defined compounds which are useful for treatingasthma, allergic diseases, inflammation and diabetes in mammals. Theinvention also comprises processes of preparing the compounds within thescope of the above formula.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention are obtainable ascrystalline materials having characteristic melting points andabsorption spectra. They are in general sparingly soluble in organicsolvents such as lower alkanols, chloroform, tetrahydrofuran,N,N-dimethylformamide, dichloromethane, acetone and the like, but aregenerally insoluble in water.

The novel 4,5,6-substituted-2-pyrimidinamines of the present inventionin general may be prepared as set forth in the following reactionschemes. ##STR3## wherein R₁, R₂, R₃, R₄ and R₅ are as hereinabovedefined.

In accordance with Scheme I, a heteroaryl (R₃) alkanoyl (R₄) compound 1,e.g 2-acetylpyridine, 2-acetylfuran, 3-acetylthiophene,2-acetyl-6-methylpyridine, 2-propionyl pyridine or 3-propionyl pyridineand the like, is reacted with a di(lower alkyl)-formamide or acetamidedi(lower alkyl) acetal 2, e.g; N,N-dimethylformamide dimethylacetal orN,N-dimethylacetamide dimethylacetal at an elevated temperature in therange of about 50° C. to about 150° C. for from about 4 to 24 hours toproduce the 3di(lower alkyl)aminoacrylophenone 3. The acrylophenone 3 isthen reacted with an appropriately substituted phenylguanidine (R₁)(R₂), 4 as the base or as the carbonate, sulfate, nitrate, hydrochlorideor dihydrochloride salt in an inert solvent such as absolute ethanol,n-propanol, isopropyl alcohol or 2-methoxyethanol and the like, byheating at the reflux temperature for from 6-48 hours. The product 5 isseparated by the partial evaporation of the solvent, then cooling andcollected and recrystallized in a conventional manner from solvents suchas n-propyl alcohol, isopropyl alcohol, absolute ethyl alcohol or2-methoxyethanol and the like and combinations of solvents such aschloroform/hexane, dichoromethane/hexane or isopropyl alcohol/ethyleneglycol monomethyl ether and the like. ##STR4## wherein R₁, R₂, R₃, R₄and R₅ are as hereinabove defind.

In accordance with Scheme II, when the4,5,6-substituted-2-pyrimidinamine product 5 is dissolved by heating ina solvent such as absolute ethanol, isopropyl alcohol ordichloromethane, then stirred at room temperature and reacted with amineral acid such as sulfuric acid, hydrochloric acid, nitric acid orphosphoric acid and the like, dissolved in absolute ethanol or isopropylalcohol and the like, the 4,5,6-substituted-2-pyrimidinamine acidaddition salt 6 is precipitated on standing for 30 minutes and chillingfor several hours.

Alternatively, acid addition salts may be formed with organic aciddssuch as citric acid or maleic acid and the like by dissolving thedesired 4,5,6-substituted-2-pyrimidinamine in hot, absolute ethanol or2-methoxyethanol in the presence of the organic acid. Cooling providesthe desired compounds as solids.

The novel compounds of the present invention are highly active asantiasthmatic and antiallergic agents as will be demonstratedhereinbelow.

The bromochospasm of allergic asthma is a consequence of the release ofmediators, such as histamine and slow-reacting substances from mastscells. The role of mediator release in the induction of an asthmaticattack has been fully reviewed and documented; see Kaliner, M. andAusten, K. F., Bronchial Asthma Mechanisms and Therepautics, E. B.Weiss, Editor, Little, Brown and Company, Boston, 163, (1976);Lichtenstein, L. M., Asthma-Physiology, Immunopharmacology andTreatment, Second International Symposium, L. M. Lichtenstein and K. F.Austen, Editors, Academic Press, New York, 51, (1979); and Bell, S. C.,et al., Annular Reports in Medicinal Chemistry, 14, 51, H, J. Hess,Editor, Academic Press, New York, (1979),

The novel compounds of this invention have been tested by the procedureof Lichtenstein, L. M. and Osler, A. G., J. Exp. Med., 120, 507-530(1964), which evaluates the ability of compounds to inhibit mediator(histamine) release from immunologically stimulated human basophils.

Reagents 10X Concentrated Tris Buffer

Dissolve 140.3 g of sodium chloride, 7.45 g of Trizma-Tris Pre-Set,Reagent Grade, pH 7.6, at 25° C. (Sigma Chemical Co.) in sufficientwater to give a final volume of 2 liters.

Human Albumin

(Sigma Chemical Co.) (30 mg/ml)

Calcium and Magnesium Stocks

Made to 0.075M 0.5M respectively, with calcium chloride dihydrate andmagnesium chloride hexahydrate.

Tris-A Buffer A 10 ml portion of 10X Tris Buffer and 1.0 ml of humanalbumin are diluted to 100 ml with water. Tris ACM Buffer

A 10 ml portion of 10X Tris Buffer, 1.0 ml of human albumin, 0.8 ml ofcalcium stock and 0.2 ml of magnesium stock are diluted to 100 ml withwater.

Rabbit Antihuman IgE

Behring Diagnostics (Generally used at 10 μg protein/ml finalconcentration).

House Dust Mite Extract (Dermatophagoides Farinae)

Strength 1:100 (w:v) allergenic extract, Hollister-Stier Labs. Generallythis is diluted 1:1000 to 1:10,000 (considering the vial as stock).

Other Allergens

Interdermal solutions or intramuscular preparations forhyposensitization, Hollister-Steir Labs. The final concentration used ison the order of 1 PNU/ml.

Separation of Leukocytes from Human Blood and Challenge

Eighty milliliters of blood is withdrawn from subjects with knownhistamine release to anti-IgE, ragweed antigen or other specificallergen, using four 20 ml heparinized tubes. This 80 ml of blood ismixed with 20 ml of saline containing 0.6 g dextrose and 1.2 g ofdextran. The blood is allowed to sediment at room temperature in two 50ml polycarbonate centrifuge tubes until a sharp interface developsbetween the red cells and plasma (60-90 minutes). The plasma (top) layerfrom each tube is withdrawn by pipet and transferred to respective 50 mlpolycarbonate tubes. The plasma is centrifuged for 8 minutes at 110X Gat 4° C. The supernatant is carefully poured off as completely aspossible and the cell button is resuspended in 2-3 ml of Tris-A bufferusing a siliconized Pasteur pipet. The resuspension is accomplished bydrawing the liquid gently in an out of the pipet, with the tip below theliquid until an even suspension of cells is obtained. SufficientTris-A-buffer is then added to bring the volume in the tube to about 45ml and the tube is centifuged at 110X G for 8 minutes at 4° C. Thesupernatant is poured off and the cell button is resuspended andcentrifuged as described above. The supernatant is poured off and thecell button is suspended in 2-3 ml of Tris-ACM buffer to make the finalvolume sufficient to allow addition to the reaction tubes.

Reaction tubes containing anti-IgE or antigens, either alone or withtest compound in a total volume of 0.2 ml are prepared and placed in a37° C. bath. The cells are warmed to 37° C. and frequently swirled toensure an even suspension, while 1.0 ml aliquots are added to eachreaction tube. The tubes are then incubated for 60 minutes at 37° C.,vortexing the tubes gently every 15 minutes to keep the cells evenlysuspended. When the reaction is complete, the tubes are centrifuged at4° C. for 10 minutes at 1500 rpm to sediment the cells. One ml aliquotsof supernatant are transferred to 12 mm by 75 mm polyethylene tubes and0.2 ml of 8% perchloric acid is added to each tube. Blanks and totalsare included in each test. The blanks have cells and all reagents exceptantigen or anti-IgE. The totals contain 0.24 ml of 8% perchloric acid,one ml of cells and 0.2 ml of buffer. All samples are the centrifuged toremove the precipitate protein.

Assay of Released Histamine by the Automated Fluorometric Method

This automated method has been described by Siraganian, R. P., in Anal.Biochem., 57, 383 (1974) and J. Immunol. Methods, 7, 283 (1975) and isbased on the manual method of Shore, P. A., et al., J. Pharmacol. Exp.Ther., 217, 182 (1959).

The automated system consists of the following Technicon Autoanalyzer IIcomponents: Sampler IV, Dual-Speed Proportioning Pump III,Fluoronephelometer with a narrow pass primary filter 7-60 and asecondary filter 3-74, Recorder, and Digital Printer. The manifold usedis the one described by Siraganian vide supra, with the followingmodifications: the dialyzer is omitted; all pumping tubes pass through asingle proportioning pump with large capacity and twice the volume ofsample is taken for analysis.

The automated chemistry consists of the following steps: Extraction fromalkaline saline into butanol, back extraction into dilute hydrochloricacid by addition of heptane, reaction of histamine witho-phthaldialdehyde (OPT) at high pH and conversion of the OPT adduct toa stable fluorophore with phosphoric acid. The reaction product is thenpassed through the fluorometer. The full scale response is adjusted to50 ng histamine base with a threshold sensitivity of approximately 0.5ng.

Calculation of the Results of Histamine Release Tests

The instrument blank (wash) is substracted from the ng histamine of eachsample. Then the ng histamine of each sample is divided by the mean ofthe three totals (cells lysed with perchloric acid) to obtain percentrelease.

Control samples contain antigen but no test compound. Blank (orspontaneous release) samples contain neither antigen nor test compound.The means of the blanks (three replicates) is subtracted from thepercent release for controls and test compounds.

The means for control and test compound groups are computed and theresult for a test compound is computed as percent of control by theformula: ##EQU1##

Values obtained at different concentrations of test compound are used tocalculate an IC₅₀ (the concentration in μM which causes a 50% inhibitionof histamine release) by linear regression. A compound is consideredactive if the IC₅₀ is ≧48 μM.

The results of this test on typical compounds of this invention appearin Table I.

                  TABLE I                                                         ______________________________________                                        Inhibition of Histamine Release from                                          Immunologically Stimulated Human Basophils                                    Compound                   IC.sub.50 (μM)                                  ______________________________________                                        4-(2-Furanyl)-5-methyl- .sub.--N--phenyl-2-pyrimidin-                                                    17.7                                               amine                                                                         4-(4-Pyridinyl)- .sub.--N--[(3-trifluoromethyl)phenyl]-                                                  32.0                                               2-pyrimidinamine                                                               .sub.--N--(4-Methoxyphenyl)-4-(3-pyridinyl)-2-                                                          1.4                                                pyrimidinamine                                                                 .sub.--N--Phenyl-4-(3-pyridinyl)-2-pyrimidinamine                                                       0.9                                                 .sub.--N--(4-Acetylphenyl)-4-(3-pyridinyl)-2-                                                           0.8                                                pyrimidinamine                                                                 .sub.--N--(4-Fluorophenyl)-4-(3-pyridinyl)-2-                                                           <48                                                pyrimidinamine                                                                 .sub.--N--(4-Methoxyphenyl)-4-(2-pyridinyl)-2-pyrimi-                                                   8.3                                                dinamine                                                                       .sub.--N--(4-Methoxyphenyl)-4-(4-pyridinyl)-2-pyrimi-                                                   1.0                                                dinamine                                                                       .sub.--N--(4-Fluorophenyl)-4-(4-pyridinyl)-2-pyrimi-                                                    1.9                                                dinamine                                                                       .sub.--N--(4-Bromophenyl)-4-(3-pyridinyl)-2-pyrimi-                                                     2.3                                                dinamine                                                                      4-(3-Pyridinyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-                                                  0.7                                                2-pyrimidinamine, hydrochloride                                               4-(2-Pyridinyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-                                                  2.9                                                2-pyrimidinamine                                                               .sub.--N--(4-Methoxyphenyl)-4-(2-thienyl)-2-pyrimi-                                                     3.9                                                dinamine                                                                       .sub.--N--(4-Ethylphenyl)-4-(1-methyl- .sub.-- .sub.--1H--pyrrol-2-                                     <48                                                yl)-2-pyrimidinamine                                                           .sub.--N--Phenyl-4-(2-thienyl)-2-pyrimidinamine                                                         31.7                                                .sub.--N--(3-Chloro-4-methylphenyl)-4-(3-pyridinyl)-2-                                                  9.3                                                pyrimidinamine                                                                 .sub.--N--(3-Methylphenyl)-4-(2-pyridinyl)-2-pyrimi-                                                    0.7                                                dinamine                                                                       .sub.-- N--(3-Methylphenyl)-4-(4-pyridinyl)-2-pyrimi-                                                   9.4                                                dinamine                                                                       .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine                                                       0.9                                                 .sub.--N--(3-Methylphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                    1.5                                                dinamine                                                                       .sub.--N--(4-Ethylphenyl)-4-(4-pyridinyl)-2-pyrimi-                                                     7.7                                                dinamine                                                                       .sub.--N--(4-Ethylphenyl)-5-methyl-4-(4-pyridinyl)-2-                                                   <48                                                pyrimidinamine                                                                 .sub.--N--4-Ethylphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                      <48                                                dinamine                                                                       .sub.--N--(4-Ethylphenyl)-4-(2-pyridinyl)-2-pyrimi-                                                     2.1                                                dinamine                                                                       .sub.--N--(3-Methylphenyl)-4-(2-thienyl)-2-pyrimi-                                                      0.3                                                dinamine                                                                      4-(2-Furanyl)- .sub.--N--phenyl-2-pyrimidinamine                                                         48                                                 4-(2-Furanyl)- .sub.--N--(3-methylphenyl)-2-pyrimi-                                                      3.5                                                dinamine                                                                       .sub.--N--(4-Ethylphenyl)-4-(6-methyl-3-pyridinyl)-2-                                                   13.4                                               pyrimidinamine                                                                 .sub.--N--(4-Ethylphenyl)-6-methyl-4-(6-methyl-3-                                                       19.1                                               pyridinyl)-2-pyrimidinamine                                                    .sub.--N--[4-(4-Methyl-1-piperazinyl)phenyl]-4-(2-                                                      <24                                                thienyl)-2-pyrimidinamine                                                      .sub.--N--(4-Ethylphenyl)-4-pyrazinyl-2-pyrimidinamine                                                  2.8                                                 .sub.--N--(3-Methylphenyl)-4-pyrazinyl-2-pyrimi-                                                        5.4                                                dinamine                                                                       .sub.--N--(2-Methylphenyl)-4-(4-pyridinyl)-2-pyrimi-                                                    3.9                                                dinamine                                                                       .sub.--N--(3-Ethylphenyl)-4-(4-pyridinyl)-2-pyrimi-                                                     10.6                                               dinamine                                                                       .sub.--N--(2,5-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                       47.1                                               pyrimidinamine                                                                 .sub.--N--(2,3-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                       20.2                                               pyrimidinamine                                                                 .sub.--N--(3-Methylphenyl)-4-(3-thienyl)-2-pyrimidin-                                                   3.8                                                amine                                                                          .sub.--N--(2,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                       <48                                                pyrimidinamine                                                                 .sub.--N--(3,5-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                       4.4                                                pyrimidinamine                                                                   .sub.--N-- 1-Naphthalenyl-4-(4-pyridinyl)-2-pyrimidin-                                                31.3                                               amine                                                                          .sub.--N--(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                       1.0                                                pyrimidinamine                                                                 .sub.--N-- 1-Naphthalenyl-4-(2-pyridinyl-2-pyrimidin-                                                   3.0                                                amine                                                                          .sub.--N--(2,4-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                       24.0                                               pyrimidinamine                                                                4-(4-Pyridinyl)- .sub.--N--(2,4,6-trimethylphenyl)-2-                                                    10.5                                               pyrimidinamine                                                                4-(2-Furanyl)- .sub.--N--(4-methoxyphenyl)-2-pyrimidin-                                                  <48                                                amine                                                                          .sub.--N--[4-(4-Methyl-1-piperazinyl)phenyl]-4-(2-                                                      <24                                                pyridinyl)-2-pyrimidinamine                                                   4-(2-Furanyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-2-                                                  <48                                                pyrimidinamine                                                                 .sub.--N--(4-Fluorophenyl)-4-(2-furanyl)-2-pyrimidin-                                                   13.3                                               amine                                                                          .sub.--N--Cyclopentyl-4-(2-pyridinyl)-2-pyrimidinamine                                                  2.2                                                 .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                      3.5                                                compound with 2-hydroxy-1,2,3-propanetricar-                                  boxylate (2:1)                                                                 .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                      1.0                                                (Z)-2-butenedioate (1:1)                                                       .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                      3.0                                                sulfate                                                                        .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                      1.2                                                dinitrate                                                                      .sub.--N--(4-Ethylphenyl)-4-(4-pyridinyl)-2-pyrimidin-                                                  17.7                                               amine, pyridine-1-oxide                                                        .sub.--N--(3,4-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                       5.9                                                pyrimidinamine                                                                 .sub.--N--(4-Methoxyphenyl)-4-(3-thienyl)-2-pyrimidin-                                                  15.6                                               amine                                                                          .sub.--N--(3-Ethylphenyl)-4-(2-furanyl)-2-pyrimidin-                                                    9.7                                                amine                                                                         4-(1 .sub.--H--Indol-3-yl)- .sub.--N--phenyl-2-pyrimidinamine                                            3.0                                                  .sub.--N--(2-Methoxy-5-methylphenyl)-4-(4-pyridinyl)-                                                  6.9                                                2-pyrimidinamine                                                               .sub.--N--(3-Methylphenyl)-4-(1-methyl-1 .sub.--H--pyrrol-2-                                            9.4                                                yl)-2-pyrimidinamine                                                           .sub.--N--(3-Ethylphenyl)-4-(2-thienyl)-2-pyrimidin-                                                    48.0                                               amine                                                                          .sub.--N--(3-Ethylphenyl)-4-(3-thienyl)-2-pyrimidin-                                                    1.1                                                amine                                                                         4-(1 .sub.--H--Indol-2-yl)- .sub.--N--(3-methylphenyl)-2-pyrimi-                                         2.2                                                dinamine                                                                      4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]-                                                                27.5                                               benzoic acid, methyl ester                                                     .sub.--N--(3-Methylphenyl)-4-(4-quinolinyl)-2-pyrimi-                                                   10.9                                               dinamine                                                                       .sub.--N--Phenyl-4-(-4-quinolinyl)-2-pyrimidinamine                                                     3.0                                                 .sub.--N--(4-Ethylphenyl)-4-(4-quinolinyl)-2-pyrimi-                                                    4.0                                                dinamine                                                                      4-(2-Pyridinyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-                                                  3.0                                                2-pyrimidinamine, sulfate                                                      .sub.--N--(3-Methylphenyl)-4-(2-thienyl)-2-pyrimidin-                                                   3.0                                                amine, sulfate                                                                4-(2-Furanyl)- .sub.--N--[3-(methylphenyl)]-2-pyrimi-                                                    3.0                                                dinamine, sulfate                                                              .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                      3.3                                                phosphate                                                                      .sub.--N--(3,5-Dimethylphenyl)-4-(2-furanyl)-2-pyrimi-                                                  0.7                                                dinamine                                                                       .sub.--N--(3,5-Dimethylphenyl)-4-(2-thienyl)-2-pyrimi-                                                  4.3                                                dinamine                                                                       .sub.--N--(2,4-Difluorophenyl)-4-(4-pridinyl)-2-                                                        <48                                                pyrimidinamine                                                                 .sub.--N--(2,4-Difluorophenyl)-4-(3-pyridinyl)-2-                                                       <48                                                pyrimidinamine                                                                 .sub.--N--(3-Methylphenyl)-4-(5-methyl-2-thienyl)-                                                      1.4                                                2-pyrimidinamine                                                               .sub.--N--(2,6-Difluorophenyl)-4-(4-pyridinyl)-2-                                                       2.9                                                pyrimidinamine                                                                4-(4-Pyridinyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-                                                  < 48                                               2-pyrimidinamine, sulfate                                                      .sub.--N--(4-Methoxyphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                   <48                                                dinamine, sulfate                                                              .sub.--N--Phenyl-4-(3-pyridinyl)-2-pyrimidinamine,                                                      3.0                                                sulfate                                                                       4-(3-Pyridinyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-                                                  2.6                                                2-pyrimidinamine, sulfate                                                      .sub.--N-- Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                     3.0                                                dihydrochloride                                                                .sub.--N--[4-(1,1-Dimethylethyl)phenyl]-4-(3-pyridin-                                                   0.7                                                yl)-2-pyrimidinamine                                                           .sub.--N--(2,6-Difluorophenyl)-4-(3-pyridinyl)-2-                                                       22.0                                               pyrimidinamine                                                                 .sub.--N--(4-Ethylphenyl)-4-(5-methyl-2-thienyl)-2-                                                     36.3                                               pyrimidinamine                                                                 .sub.--N--[(3,4-Dimethylphenyl)methyl]-4-(2-pyridinyl-                                                  39.8                                               2-pyrimidinamine                                                               .sub.--N--(3,5-Dimethylphenyl)-4-(3-pyridinyl)-2-                                                       3.0                                                pyrimidinamine, sulfate                                                        .sub.--N--(3,5-Dimethylphenyl)-4-(3-pyridinyl)-2-                                                       3.0                                                pyrimidinamine, phosphate                                                      .sub.--N--(3-Methylphenyl)-4-(1 .sub.--H--pyrrol-2-yl)-2-                                               11.1                                               pyrimidinamine                                                                4-(5-Methyl-2-furanyl)- .sub.--N--(3-methylphenyl)-2-                                                    2.0                                                pyrimidinamine                                                                4-Methyl-6-(5-methyl-2-thienyl)- .sub.--N--phenyl-2-                                                     24.8                                               pyrimidinamine                                                                 .sub.--N--[4-(Dimethylamino)phenyl]-4-(4-pyridinyl)-2-                                                  3.8                                                pyrimidinamine                                                                 .sub.--N--(3-Methoxyphenyl)-4-(4-pyridinyl)-2-pyrimi-                                                   0.4                                                dinamine                                                                       .sub.--N--(3-Methoxyphenyl)-4-(2-pyridinyl)-2-pyrimi-                                                   0.2                                                dinamine                                                                       .sub.--N--[4-(Dimethylamino)phenyl]-4-(2-pyridinyl)-2-                                                  2.7                                                pyrimidinamine                                                                 .sub.--N--(3-Methoxyphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                   0.3                                                dinamine                                                                       .sub.--N--(3,5-Dimethylphenyl)-4-(3-pyridinyl)-2-                                                       0.8                                                pyrimidinamine                                                                4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                                12.4                                               benzoic acid, ethyl ester                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-pyridinyl)-2-pyrimidin-                                  3.7                                                yl]-1,4-benzenediamine                                                        4-(2,5-Dimethyl-3-furanyl)- .sub.--N--phenyl-2-pyrimi-                                                   2.0                                                dinamine                                                                       .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-pyridinyl)-2-pyrimi-                                     0.4                                                dinyl)benzenediamine, trihydrochloride                                        4-(2,5-Dimethyl-3-furanyl)- .sub.--N--(3-methylphenyl)-                                                  28.5                                               2-pyrimidinamine                                                              4-(2,5-Dimethyl-3-furanyl)- .sub.--N--(3,5-dimethyl-                                                     4.1                                                phenyl-2-pyrimidinamine                                                        .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-pyridinyl)-2-pyrimidin-                                  4.4                                                yl]-1,4-benzenediamine, dihydrochloride                                       4-(2,5-Dimethyl-3-furanyl)- .sub.--N--(4-ethylphenyl)-                                                   19.2                                               2-pyrimidinamine                                                               .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-pyridinyl)-2-pyrimi-                                     1.7                                                dinyl]-1,3-benzenediamine                                                     3-[[4-(2-Pyridinyl)-2-pyrimidinyl]amino]ben-                                                             3.0                                                zoic acid, ethyl ester                                                         .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-pyridinyl)-2-pyrimidin-                                  0.5                                                yl]-1,3-benzenediamine                                                        4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenol                                                           5.1                                                3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]ben-                                                             20.3                                               zoic acid, ethyl ester                                                         .sub.--N--(4-Methoxyphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                   3.2                                                dinamine, phosphate                                                            .sub.--N--(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                       0.6                                                pyrimidinamine, sulfate                                                        .sub.--N--[4-(2-Propenyloxy)phenyl]-4-(3-pyridinyl)-2-                                                  0.8                                                pyrimidinamine                                                                 .sub.--N--[4-[2-(Dimethylamino)ethoxy]phenyl]-4-                                                        0.5                                                (3-pyridinyl)-2-pyrimidinamine                                                 .sub.--N--Phenyl-4-(3-pyridinyl)-2-pyrimidinamine,                                                      2.7                                                phosphate                                                                      .sub.--N'--[4-(2-Furanyl)-2-pyrimidinyl]- .sub.--N, .sub.--N--                                          1.9                                                dimethyl-1,4-benzenediamine                                                    .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-thienyl)-2-pyrimidinyl]                                  0.6                                                1,4-benzendiamine                                                              .sub.--N'--[4-(2,5-Dimethyl-3-furanyl)-2-pyrimidinyl]-                                                  4.9                                                 .sub.--N, .sub.--N--dimethyl-1,4-benzenediamine                               .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-methyl-2-thienyl)-2-                                     1.8                                                pyrimidinyl]-1,4-benzenediamine                                                .sub.--N--(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                       0.3                                                pyrimidinamine, phosphate                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-pyridinyl)-2-pyrimidin-                                  1.5                                                yl]-1,4-benzenediamine, trihydrochloride                                       .sub.--N, .sub.--N-- Dimethyl- .sub.--N'--[4-(4-pyridinyl)-2-pyrimidin-                                 3.5                                                yl]-1,3-benzenediamine                                                         .sub.--N, .sub.--N--Dimethyl-  .sub.--N'--[4-methyl-6-(4-pyridinyl)-2-                                  37.7                                               pyrimidinyl]-1,4-benzenediamine                                                .sub.--N--[4-[3-Dimethylamino)propoxy]phenyl]-4-(3-                                                     0.5                                                pyridinyl)-2-pyrimidinamine                                                    .sub.--N--[4-[2-Diethylamino)ethoxy]phenyl]-4-(3-                                                       0.2                                                pyridinyl)-2-pyrimidinamine                                                    .sub.--N--[4-[ 2-Dimethylamino)ethoxy]phenyl]-4-(3-                                                     0.5                                                pyridinyl)-2-pyrimidinamine, hydrochloride                                    4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]ben-                                                             7.6                                                zoic acid                                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-pyridinyl)-2-pyrimidin-                                  0.5                                                yl]-1,3-benzenediamine, dihydrochloride                                        .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-pyridinyl)-2-pyrimidin-                                  1.0                                                yl]-1,3-benzenediamine, trihydrochloride                                       .sub.--N--(3,5-Dimethylphenyl)-4-(2-furanyl)-5-methyl-                                                  <24                                                2-pyrimidinamine                                                               .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-pyridinyl)-2-pyrimidin-                                  0.5                                                yl]-1,3-benzenediamine, dihydrochloride                                        .sub.--N'--[4-(2-Furanyl)-5-methyl-2-pyrimidinyl]- .sub.--N, .sub.--N--                                 6.1                                                dimethyl-1,4-benzenediamine                                                   4-(2-Furanyl)-5-methyl- .sub.--N--phenyl-2-pyrimidin-                                                    5.0                                                amine, sulfate                                                                 .sub.--N'--[4-(2-Benzofuranyl)-2-pyrimidinyl]- .sub.--N, .sub.--N--                                     5.6                                                methyl-1,4-benzenediamine                                                     4-Methyl- .sub.--N--phenyl-6-(2-pyridinyl)-2-pyrimi-                                                     26.8                                               dinamine                                                                      4-[[4-(4-(Pyridinyl)-2-pyrimidinyl]amino]-                                                               3.3                                                phenol                                                                         .sub.--N--[4-[2-(Dimethylamino)ethoxy]phenyl]-4-(4-                                                     1.5                                                pyridinyl)-2-pyrimidinamine                                                    .sub.--N--[4-[2-(Dimethylamino)ethoxy]phenyl] .sub.--N', .sub.--N'--                                    9.1                                                dimethyl- .sub.--N--[4-(4-pyridinyl)-2-pyrimidinyl]-                          1,2-ethanediamine                                                              .sub.--N--[4-[3-Dimethylamino)propoxy]phenyl]-4-(4-                                                     1.3                                                pyridinyl)-2-pyrimidinamine                                                    .sub.--N--[4-[2-(Diethylamino)ethoxy]phenyl]-4-(4-                                                      0.2                                                pyridinyl)-2-pyrimidinamine                                                   4-[2-[(4-Methoxyphenyl)amino]-4-pyrimidinyl]-                                                            33.3                                               1-methylpyridinium, iodide                                                     .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-pyridinyl)-2-pyrimi-                                     1.0                                                dinyl)]-1,3-benzenediamine, sulfate                                            .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-thienyl)-2-pyrimidinyl]-                                 2.4                                                1,3-benzenediamine                                                             .sub.--N, .sub.--N--Dimethyl-- .sub.--N'--[4-(5-methyl-2-furanyl)-2-                                    1.6                                                pyrimidinyl]-1,3-benzenediamine                                                .sub.--N'--[4-(2,5-Dimethyl-3-furanyl)-2-pyrimidinyl]-                                                  <24                                                 .sub.--N, .sub.--N--dimethyl-1,3-benzenediamine                               .sub. --N--[2-(Diethylamino)ethyl]-4-[[4-(3-pyridin-                                                    0.8                                                yl)-2-pyrimidinyl]amino]benzamide                                             4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]-                                                                5.8                                                phenoxy]acetic acid, ethyl ester                                               .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(4-pyridinyl)-2-pyrimidin-                                   1.1                                                yl]-1,4-benzenediamine                                                         .sub.--N, .sub.- .sub.--N--Dimethyl- .sub.--N'--[4-methyl-6-(2-pyridinyl)    -2-                        31.8                                               pyrimidinyl]-1,4-benzenediamine                                                .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)phenyl]-4-(4-pyridin-                                           12.3                                               yl)-2-pyrimidinamine                                                           .sub.--N--[4-(4-Pyridinyl)-2-pyrimidinyl]-1,4-benzene-                                                  3.0                                                diamine, hydrochloride                                                         .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(3-pyridinyl)-2-pyrimi-                                      1.7                                                dinyl]-1,4-benzenediamine                                                      .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)phenyl]-4-(3-pyridin-                                           1.3                                                yl)-2-pyrimidinamine                                                          1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                             11.4                                               phenyl]ethanone, oxime                                                        1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                             5.1                                                phenyl]ethanone, O--methyloxime                                                .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(2-pyridinyl)-2-pyrimidin-                                   10.1                                               yl]-1,4-benzenediamine                                                         .sub.--N--[4-(1 .sub.--H-- Imidazol-1-yl)phenyl]-4-(2-pyridin-                                          1.8                                                yl)-2-pyrimidinamine                                                          4-(2-Furanyl)- .sub.--N--[4-(1 .sub.--H--imidazol-1-yl)phenyl]-                                          2.2                                                2-pyrimidinamine                                                               .sub.--N--Methyl-4-[[4-(3-pyridinyl)-2-pyrimidinyl]-                                                    4.6                                                amino]-benzamide                                                               .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(5-methyl-2-thienyl)-2-                                     5.7                                                pyrimidinyl]-1,3-benzenediamine                                                .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-thienyl)-2-pyrimidinyl]-                                 2.1                                                1,4-benzenediamine                                                             .sub.--N--[1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                       0.4                                                amino]phenyl]ethyl]formamide                                                   .sub.--N--[4-[1-Aminoethyl)phenyl]-4-(3-pyridinyl)-                                                     0.8                                                2-pyrimidinamine, trihydrochloride                                            4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]benz-                                                            0.2                                                enesulfonamide                                                                 .sub.--N--(3-Chlorophenyl)-4-(4-pyridinyl)-2-pyrimi-                                                    3.1                                                dinamine                                                                       .sub.--N--(3-Chlorophenyl)-4-(3-pyridinyl)-2-pyrimi-                                                    1.5                                                dinamine                                                                       .sub.--N--(3-Methoxyphenyl)-4-(3-thienyl)-2-pyrimidin-                                                  1.7                                                amine                                                                          .sub.--N--Methyl- .sub.--N--[4-[[4-(3-pyridinyl)-2-pyrimidin-                                           1.1                                                yl]amino]phenyl]acetamide                                                      .sub.--N--Methyl- .sub.--N--[4-[[4-(4-pyridinyl)-2-pyrimidin-                                           0.1                                                yl]amino]phenyl]acetamide                                                      .sub.--N--Methyl- .sub.--N--[4-[ [4-(2-pyridinyl)-2-pyrimidin-                                          0.6                                                yl]amino]phenyl]acetamide                                                     [4-(2-Furanyl)- .sub.--N--(3-methoxyphenyl)-2-pyrimi-                                                    0.3                                                dinamine                                                                      4-(2-Benzofuranyl)- .sub.--N--(3-methoxyphenyl)-2-                                                       1.2                                                pyrimidinamine                                                                Oxo[phenyl[4-(4-pyridinyl)-2-pyrimidinyl]-                                                               2.1                                                amino]acetic acid, ethyl ester                                                 .sub.--N--[4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]-                                                    5.3                                                phenyl]acetamide                                                               .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-furanyl)-5-methyl-2-                                     40                                                 pyrimidinyl]-1,3-benzenediamine                                                .sub.--N--[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                    3.6                                                phenyl]acetamide                                                              4-[[4-(2-Pyridinyl)-2-pyrimidinyl]amino]-                                                                4.5                                                benzenesulfonamide                                                             .sub.--N--[4-[[4-(2-Pyridinyl)-2-pyrimidinyl]amino]-                                                    1.5                                                phenyl]acetamide                                                               .sub.--N--(3-Methoxyphenyl-4-(2-thienyl)-2-pyrimi-                                                      0.9                                                dinamine                                                                       .sub.--N--[4-(4-Methyl-1-piperazinyl)phenyl]-4-(3-                                                      1.5                                                pyridinyl)-2-pyrimidinamine                                                    .sub.--N--(3-Methoxyphenyl)-4-(5-methyl-2-thienyl)-                                                     2.3                                                2-pyrimidinamine                                                               .sub.--N--(3-Chlorophenyl)-4-(2-pyridinyl)-2-pyrimi-                                                    1.3                                                dinamine                                                                      4-(2-Furanyl)- .sub.--N--[4-(4-methyl-1-piperazinyl)-                                                    1.8                                                phenyl]-2-pyrimidinamine                                                       .sub.--N--[4-(4-Methyl-1-piperazinyl)phenyl]-4-(4-                                                      0.6                                                pyridinyl)-2-pyrimidinamine                                                    .sub.--N--(3-Methoxyphenyl)-4-(2,5-dimethyl-3-furan-                                                    5.8                                                yl)-2-pyrimidinamine                                                           .sub.--N--[4-(2-Pyridinyl)-2-pyrimidinyl]-1,4-benzene-                                                  1.0                                                diamine, dihydrochloride                                                       .sub.--N--(3-Fluorophenyl)-4-(4-pyridinyl)-2-pyrimi-                                                    0.7                                                dinamine                                                                       .sub.--N--(3-Fluorophenyl)-4-(3-pyridinyl)-2-pyrimi-                                                    3.3                                                dinamine                                                                       .sub.--N--(3-Fluorophenyl)-4-(2-pyridinyl)-2-pyrimi-                                                    0.9                                                dinamine                                                                      1-[3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                             4.1                                                phenyl]ethanone                                                                .sub.--N--Methyl- .sub.--N'--[4-(3-pyridinyl)-2-pyrimidinyl]-                                           2.1                                                1,4-benzenediamine                                                             .sub.--N--[4-(1-Methylethyl)phenyl]-4-(3-pyridinyl)-                                                    1.1                                                2-pyrimidinamine                                                               .sub.--N--Methyl- .sub.--N'--[4-(2-pyridinyl)-2-pyrimidinyl]-                                           1.4                                                1,4-benzenediamine                                                             .sub.--N--(3-Ethylphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                     1.7                                                dinamine                                                                       .sub.--N--(3-Ethylphenyl)-4-(2-pyridinyl)-2-pyrimi-                                                     1.4                                                dinamine                                                                      3-[[4-(2-Pyridinyl)-2-pyrimidinyl]amino]ben-                                                             0.7                                                zenesulfonamide                                                               3-[[4-(3-Pyridiny)-2-pyrimidinyl]amino]ben-                                                              0.2                                                zenesulfonamide                                                                .sub.--N--[4-(1,1-Dimethylethyl)phenyl]-4-(2-thienyl)-                                                  4.6                                                2-pyrimidinamine                                                               .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(2-furanyl)-2-pyrimidinyl]-                                  3.4                                                1,4-benzenediamine                                                            3-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]-                                                                0.5                                                benzenesulfonamide                                                             .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-pyridinyl)-2-pyrimi-                                     36.2                                               dinyl]-1,2-benzenediamine, fumarate                                           2-[1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]                                                           8.1                                                phenyl]ethylidene]hydrazinecarboxamide                                         .sub.--N--[4-[2-[bis(1,1-Dimethylethyl)amino]ethoxy]-                                                   4.6                                                phenyl]-4-(3-pyridinyl)-2-pyrimidinamine                                      α-Methyl-4-[ [4-(3-pyridinyl)-2-pyrimidinyl]-                                                      4.5                                                amino]benzenemethanol                                                          .sub.--N--[1-[3-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                       4.6                                                amino]phenyl]ethyl]formamide                                                   .sub.--N--[3-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]-                                                    2.1                                                phenyl]acetamide                                                               .sub.--N--[3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                    5.0                                                phenyl]acetamide                                                               .sub.--N--[4-(3-Pyridinyl)-2-pyrimidinyl]-1,3-benzene-                                                  0.4                                                diamine, dihydrochloride                                                       .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(5-methyl-2-furanyl)-2-                                      28.0                                               pyrimidinyl]1,4-benzenediamine                                                 .sub.--N--(3-Methoxyphenyl)-4-(5-methyl-2-furanyl)-2-                                                   1.2                                                pyrimidinamine                                                                 .sub.--N--[3-[[4-(2-Pyridinyl)-2-pyrimidinyl]amino]-                                                    0.3                                                phenyl]acetamide                                                               .sub.--N--[3-(1 .sub.--H--Imidazol-1-yl)phenyl]-4-(2-pyri-                                              0.1                                                dinyl)-2-pyrimidinamine                                                        .sub.--N--[4-(4-Pyridinyl)-2-pyrimidinyl]-1,3-benzene-                                                  1.0                                                diamine                                                                        .sub.--N--[2-Methyl-4-[[4-(4-pyridinyl)-2-pyrimi-                                                       1.2                                                dinyl]amino]phenyl]acetamide                                                  2-Methyl- .sub.--N--[4-(4-pyridinyl)-2-pyrimidinyl]-                                                     0.9                                                1,4-benzenediamine, dihydrochloride                                            .sub.--N--[4-(2-Pyridinyl)-2-pyrimidinyl]-1,3-benzen-                                                   0.2                                                diamine                                                                        .sub.--N--[4-[[4-(5-Methyl-2-thienyl)-2-pyrimidinyl]-                                                   0.3                                                amino]phenyl]acetamide                                                         .sub.--N--[ 3-(1-Aminoethyl)phenyl]-4-(3-pyridinyl)-2-                                                  5.1                                                pyrimidinamine, trihydrochloride                                               .sub.--N--[3-[2-(Diethylamino)ethoxy]phenyl]-4-(3-                                                      2.8                                                pyridinyl)-2-pyrimidinamine                                                    .sub.--N--(2-Methoxyphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                   9.8                                                dinamine                                                                       .sub.--N--[4-[[4-(2-Thienyl)-2-pyrimidinyl]amino]-                                                      0.2                                                phenyl]acetamide                                                               .sub.--N--[2-Methyl-4-[4-(3-pyridinyl)-2-pyrimidinyl]-                                                  1.8                                                phenyl]acetamide                                                               .sub.--N'--[4-(2-Benzofuranyl)-2-pyrimidinyl]- .sub.--N, .sub.--N--                                     6.2                                                diethyl-1,4-benzenediamine                                                     .sub.--N--[4-[[4-(2-Furanyl)-2-pyrimidinyl]amino]-                                                      0.7                                                phenyl]acetamide                                                               .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)-3-(trifluoromethyl)-                                           0.4                                                phenyl]-4-(4-pyridinyl)-2-pyrimidinamine                                       .sub.--N--[3-(1 .sub.-- .sub.--H--Imidazol-1-yl)phenyl]-4-(3-pyri-                                      0.1                                                dinyl)-2-pyrimidinamine                                                       2-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                                23.5                                               phenol                                                                        4-(2-Furanyl)- .sub.--N--[3-(1 .sub.--H--imidazol-1-yl)phenyl]-                                          0.8                                                2-pyrimidinamine                                                               .sub.--N--[3-[2-(Diethylamino)ethoxy]phenyl]-4-(2-                                                      1.3                                                furanyl)-2-pyrimidinamine                                                      .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)-3-(trifluoromethyl)-                                           1.6                                                phenyl]-4-(2-pyridinyl)-2-pyrimidinamine                                       .sub.--N--[3-[2-(Diethylamino)ethoxy]phenyl]-4-(2-                                                      0.6                                                thienyl)-2-pyrimidinamine                                                       .sub.--N--[3-[2-(Diethylamino)ethoxy]phenyl]-4-(4-                                                     0.7                                                pyridinyl)-2-pyrimidinamine                                                    .sub.--N--[4-(4-Pyridinyl)-2-pyrimidinyl]-1,4-ben-                                                      2.4                                                zenediamine                                                                   N--[3-(1 .sub.--H--Imidazol-1-yl)phenyl]-4-(4-pyridinyl)-                                                0.4                                                2-pyrimidinamine                                                              N--[3-(1 .sub.--H--Imidazol-1-yl)phenyl]-4-(2-thienyl)-2-                                                0.2                                                pyrimidinamine                                                                ______________________________________                                    

The ability of these compounds to inhibit lipoxygenase activity in termsof the suppression of the release and biosynthesis of leukotrieneB4(LTB4) and 5-hydroxy-eicosatetraenoic acid (5-HETE) was measured asfollows.

In this assay 3×10⁷ peritoneal neutrophils derived from guinea pigs wereincubated at 37° C. in Dulbeccos buffer containing 50 mM tris buffer (pH7.4). Five minutes before the addition of 100 μM arachidonic acid and 20μM calcium ionophore (A23187), control vehicle or the test compoundswere added to the neutrophils at a concentration of 10 μg/ml.

Three minutes after the addition of arachidonic acid and calciumionophore the total lipid was partitioned into chloroform afteradjusting the pH to 3 with citric acid and the addition of equal partsof methanol and chloroform.

The 5-HETE and LTB4 were resolved by HPLC using a 5 μm 4×25 cm octadecylsilica column (IBM Instruments) with 70-80% methanol in water adjustedto pH 3.0 with acetic acid. As the mobile phase was pumped at 1.0ml/minute, LTB4 and 5-HETE were detected by absorbance of 270 and 236nm, respectively.

LTB4 and 5-HETE were quantitated by comparison with the control and theresults were expressed as a percent of control. The lower thepercentage, the more active the compound.

The results of this test on representative compounds of this inventionappear in Table II.

                  TABLE II                                                        ______________________________________                                        Inhibition of Neutrophil Lipoxygenase from                                    Immunologically Stimulated Guinea Pig Neutrophiles                                                 % Inhibition                                             Compound               LTB4    5-HETE                                         ______________________________________                                        4-(3-Pyridinyl)- .sub.--N--[3-trifluoromethyl)-                                                      58.1                                                   phenyl]-2-pyrimidinamine                                                       .sub.--N--(4-Acetylphenyl)-4-(3-pyridinyl)-2-                                                               37.0                                           pyrimidinamine                                                                 .sub.--N--(4-Fluorophenyl)-4-(2-pyridinyl)-2-                                                               45.0                                           pyrimidinamine                                                                 .sub.--N--(4-Methylphenyl)-4-(4-pyridinyl)-2-                                                               45.0                                           pyrimidinamine                                                                 .sub.--N--(4-Fluorophenyl)-4-(4-pyridinyl)-2-                                                               53.0                                           pyrimidinamine                                                                4-(3-Pridinyl)- .sub.--N--[3-trifluoromethyl)-                                                               58.0                                           phenyl]-2-pyrimidinamine                                                       .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine                                                           58.0                                            .sub.--N--(3-Methylphenyl)-4-(3-pyridinyl)-2-                                                               40.0                                           pyrimidinane                                                                   .sub.--N--[4-Ethylphenyl)-4-(4-pyridinyl)-2-                                                        33.9    41.0                                           pyrimidinamine                                                                 .sub.--N--(4-Ethylphenyl)-4-(2-pyridinyl)-2-                                                        29.5    41.0                                           pyrimidinaine                                                                 4-(2-Furanyl)- .sub.--N--(3-methylphenyl)-2-pyrimi-                                                   7.4     3.0                                           dinamine                                                                       .sub.--N--[4-(4-Methyl-1-piperazinyl)phenyl]-4-                                                     48.0                                                   (2-thienyl)-2-pyrimidinamine                                                   .sub.--N--(4-Ethylphenyl)-4-(6-methyl-3-pyridin-                                                    53.4    54.0                                           yl)-2-pyrimidinamine                                                           .sub.--N--(3-Methylphenyl)-4-pyrazinyl-2-pyrimi-                                                            50.0                                           dinamine                                                                       .sub.--N--(3-Ethylphenyl)-4-(4-pyridinyl)-2-                                                        36.4    28.7                                           pyrimidinamine                                                                 .sub.--N--(2,3-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                   58.4                                                   pyrimidinamine                                                                 .sub.--N--Phenyl-4-(3-thienyl)-2-pyrimidinamine                                                             56.0                                            .sub. --N--(3-Methylphenyl)-4-(3-thienyl)-2-pyrimi-                                                         48.0                                           dinamine                                                                       .sub.--N--(4-Ethylphenyl)-4-(3-thienyl)-2-pyrimi-                                                           56.0                                           dinamine                                                                       .sub.--N--(2,4-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                           54.0                                           pyrimidinamine                                                                 .sub.--N--(3,5-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                   53.1    54.0                                           pyrimidinamine                                                                 .sub.--N--(2-Methoxyphenyl)-4-(4-pyridinyl)-2-                                                      17.4    21.0                                           pyrimidinamine                                                                 .sub.--N--(2,5-Dimethoxyphenyl)-4-(4-pyridinyl)-                                                    43.2    47.0                                           2-pyrimidinamine                                                               .sub.--N--(2,4-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                   37.0    43.0                                           pyrimidinamine                                                                 .sub.--N--(2-Methoxy-5-methylphenyl)-4-(2-pyridin-                                                          54.0                                           yl)-2-pyrimidinamine                                                          4-(4-Pyridinyl)- .sub.--N--(2,4,6-trimethylphenyl)-                                                  53.6                                                   2-pyrimidinamine                                                              4-(2-Furanyl)- .sub.--N--(4-methoxyphenyl)-2-                                                                44.0                                           pyrimidinamine                                                                4-(2-Furanyl)- .sub.--N--[3-trifluoromethyl)-                                                        45.0    49.0                                           phenyl]-2-pyrimidinamine                                                       .sub.--N--(4-Fluorophenyl)-4-(2-furanyl)-2-pyrimi-                                                  33.0                                                   dinamine                                                                       .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                  58.0                                                   compound with 2-hydroxy-1,2,3-propanetri-                                     carboxylate (2:1)                                                              .sub.--N--[3,4-Dimethylphenyl)methyl]-4-(4-                                                         24.0    36.0                                           pyridinyl)-2-pyrimidinamine                                                    .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                  56.0                                                   sulfate                                                                       4-(2-Benzofuranyl)- .sub.--N--(3-methylphenyl)-2-                                                    46.1                                                   pyrimidinamine                                                                 .sub.--N--(4-Ethylphenyl)-4-(4-pyridinyl)-2-                                                                19.0                                           pyrimidinamine                                                                 .sub.--N--(3,4-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                           19.0                                           pyrimidinamine                                                                 .sub.--N--(3,4-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                   17.3    35.0                                           pyrimidinamine                                                                 .sub.--N--(4-Fluorophenyl)-4-(3-theinyl)-2-pyrimi-                                                  51.6                                                   dinamine                                                                      4-(10  .sub.--H--Phenothiazin-2-yl)- .sub.--N--phenyl-2-                                                     48.0                                           pyrimidinamine                                                                4-(1 .sub.--H--Indol-3-yl)- .sub.--N--phenyl-2-pyrimidin-                                            41.2    39.0                                           amine                                                                          .sub.--N--(2-Methoxy-5-methylphenyl)-4-(4-pyridin-                                                  44.7    37.0                                           yl)-2-pyrimidinamine                                                           .sub.--N--(3-Methylphenyl)-4-(1-methyl-1 .sub.--H--pyrrol-                                                  60.0                                           2-yl)-2-pyrimidinamine                                                        4-(1-Methyl-1 .sub.--H--pyrrol-2-yl) .sub.--N--phenyl)-2-                                                    57.0                                           pyridinamine                                                                   .sub.--N--(4-Ethylphenyl)-4-(1 .sub.--H--indol-3-yl)-2-                                             56.5                                                   pyridinamine                                                                   .sub.--N--[1,1'-Biphenyl]-4-yl-(4-pyridinyl)-2-                                                     37.1    45.0                                           pyrimidinamine                                                                4-[[4-(4-Pyridinyl)-2-pyrimidinyl]-amino]-                                                           45.2    47.0                                           benzoic acid, methyl ester                                                     .sub.--N--(3-Methylphenyl)-4-(4-quinolinyl)-2-                                                      16.0                                                   pyrimidinamine                                                                 .sub.--N--Phenyl-4-(4-quinolinyl)-2-pyrimidinamine                                                  46.4    57.0                                            .sub.--N--(4-Ethylphenyl)-4-(4-quinolinyl)-2-                                                               58.0                                           pyrimidinamine                                                                 .sub.--N--(3,5-Dimethylphenyl)-4-(2-furanyl)-2-                                                     56.1                                                   pyrimidinamine                                                                 .sub.--N--[(1,1-Dimethylethyl)phenyl]-4-(4-                                                         47.8    54.0                                           pyridinyl)-2-pyrimidinamine                                                    .sub.--N--Methyl- .sub.--N--phenyl-4-(2-pyridinyl)-2-                                               58.1    54.0                                           pyridinamine                                                                   .sub.--N--Phenyl-4-(1 .sub.--H--pyrrol-2-yl)-2-pyrimidin-                                           55.4                                                   amine                                                                          .sub.--N--(4-Ethylphenyl)-4-(1 .sub.-- H--pyrrol-2-yl)-2-                                           32.6    54.0                                           pyrimidinamine                                                                4-(3-Pyridinyl)- .sub.--N--[3-(trifluoromethyl)-                                                     37.3    49.0                                           phenyl]-2-pyrimidinamine sulfate                                               .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                  48.0    43.0                                           dihydrochloride                                                               4-(3-Methyl-2-thienyl)- .sub.--N--phenyl-2-pyrimi-                                                           59.0                                           dinamine                                                                      4-(5-Methyl-2-furanyl)- .sub.--N--(3-methylphenyl)-                                                  59.6                                                   2-pyrimidinamine                                                              4-Methyl-6-(5-methyl-2-thienyl)- .sub.--N--phenyl-                                                   42.3    52.0                                           2-pyrimidinamine                                                               .sub.--N--[4-(Dimethylamino)phenyl]-4-(4-pyridin-                                                   16.6    12.4                                           yl)-2-pyrimidinamine                                                           .sub.--N--(3-Methoxyphenyl)-4-(4-pyridinyl)-2-                                                      31.2    50.0                                           pyridinamine                                                                   .sub.--N--[4-(Dimethylamino)phenyl]-4-(2-pyridin-                                                   20.1    17.2                                           yl)-2-pyrimidinamine                                                           .sub.--N--(3,5-Dimethylphenyl)-4-(3-pyridinyl)-                                                     50.7    56.0                                           2-pyrimidinamine                                                              4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                            35.8    47.0                                           benzoic acid, ethyl ester                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N--'[4-(3-pyridinyl)-2-pyrimi-                                 43.4    34.0                                           dinyl]-1,4-benzenediamine                                                     4-(2,5-Dimethyl-3-furanyl)- .sub.--N--phenyl-2-                                                      46.9    56.0                                           pyridinamine                                                                   .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-pyridinyl)-2-                                        40.7    37.0                                           pyrimidinyl]-1,4-benzenediamine, trihydro-                                    chloride                                                                       .sub.--N, .sub.--N--Diemthyl- .sub.--N'--(2-pyridinyl)-2-pyrimi-                                    37.6    39.0                                           dinyl]-1,4-benzenediamine, dihydrochloride                                    4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                                    30.0                                           phenol                                                                        3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                            36.1    50.0                                           benzoic acid, ethyl ester                                                      .sub.--N--(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                   50.0                                                   pyrimidinamine, sulfate                                                        .sub.--N--[4-(2-Propenyloxy)phenyl]-4-(3-pyridin-                                                   34.1                                                   yl)-2-pyrimidinamine                                                           .sub.--N'--4-(2-Furnayl)-2-pyrimidinyl]- .sub.--N, .sub.--N--dim-                                   16.9    16.9                                           ethyl-1,4-benzenediamine                                                       .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-thienyl)-2-pyrimi-                                   49.8    17.8                                           dinyl]-1,4-benzenediamine                                                      .sub.--N'--[4-(2,5-Dimethyl-3-furanyl)-2-pyrimi-                                                    21.6    17.0                                           dinyl]- .sub.--N, .sub.--N--dimethyl-1,4-benzenediamine                        .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-methyl-2-thienyl)-                                   16.4    13.6                                           2-pyrimidinyl]-1,4-benzenediamine                                              .sub.--N, .sub.--N'--[4-(3-pyridinyl)-2-pyrimi-                                                     46.8    42.0                                           dinyl]-1,4-benzenediamine, trihydro-                                          chloride                                                                       .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-pyridinyl)-2-pyrimi-                                 51.1                                                   dinyl]-1,3-benzenediamine                                                      .sub.--N, .sub.--N-Dimethyl- .sub.--N'--[4-methyl-6-(4-pyridin-                                      1.6    10.0                                           yl)-2-pyrimidinyl]-1,4-benzenediamine                                          .sub. --N--(3,5-Dimethylphenyl)-4-methyl-6-(3-                                                      32.7    40.0                                           pyridinyl)-2-pyrimidinamine                                                    .sub.--N'--[4-(2-Furanyl)-5-methyl-2-pyrimidinyl]-                                                   3.6                                                    .sub.--N, .sub.--N--dimethyl-1,4-benzenediamine                              4-(2-Furanyl)-5-methyl- .sub.--N--phenyl-2-pyrimi-                                                   52.4                                                   dinamine, sulfate                                                              .sub.--N'--[4-(2-Benzofuranyl)-2-pyrimidinyl]- .sub.--N, .sub.--N--                                 22.9    30.0                                           dimethyl-1,4-benzenediamine                                                   4-Methyl- .sub.--N--phenyl-6-(2-pyridinyl)-2-                                                        30.3    42.0                                           pyrimidinamine                                                                4-[[4-(4-Pyridinyl)-2-pyrimidinyl]-amino]-                                                                   36.0                                           phenol                                                                         .sub.--N--(4-Methoxyphenyl)- .sub.--N--methyl-4-(4-                                                 57.4                                                   pyridinyl-2-pyrimidinamine                                                     .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-thienyl)-2-pyrimi-                                   39.6    50.0                                           dinyl]-1,3-benzenediamine                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(5-methyl-2-furanyl)-2-                                 31.1    37.7                                           pyrimidinyl]-1,3-benzenediamine                                                .sub.--N--Methyl- .sub.--N'--(2-pyridinyl)-2-pyrimi-                                                24.1    53.6                                           dinyl]-1,4-benzenediamine                                                      .sub.--N--[1-[3-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                   34.0                                                   amino]phenyl]ethyl]formamide                                                   .sub.--N--[4-[[4-(5-Methyl-2-thienyl)-2-pyrimi-                                                     51.0    46.0                                           dinyl]amino]phenyl]acetamide                                                   .sub. --N'--[4-(2-Benzofuranyl)-2-pyrimidinyl]- .sub.--N, .sub.--N--                                51.0    45.0                                           diethyl-1,4-benzenediamine                                                     .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)-3-(trifluoro-                                              20.0    16.0                                           methyl)phenyl]-4-(4-pyridinyl)-2-                                             pyrimidinamine                                                                 .sub.--N--[4-(5-Methyl-2-thienyl)-2-pyrimidinyl]-                                                   47.0    28.0                                           1,4-benzenediamine, dihydrochloride                                            .sub.--N--]3-(1 .sub.--H--Imidazol-1-yl)phenyl]-4-(3-pyri-                                          50.0    51.0                                           dinyl)-2-pyrimidinamine                                                        .sub.--N--[3-(1 .sub.--H--Imidazolyl)phenyl]-4-(2-thienyl)-                                         50.0    39.0                                           2-pyrimidinamine                                                               .sub.--N--[4-(2-Furanyl)-2-pyrimidinyl]-1,4-ben-                                                            54.0                                           zenediamine, dihydrochloride                                                   .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)-3-(trifluoro-                                                      19.0                                           methyl)phenyl]-4-(2-pyridinyl)-2-pyrimi-                                      dinamine                                                                      4-[[4-(2-Furanyl)-2-pyrimidinyl]amino]-                                                              47.0                                                   benzenesulfonamide                                                            ______________________________________                                    

The novel compounds of the present invention are effective asantiasthmatic agents in mammals when administered in amounts rangingfrom about 0.1 mg to about 100 mg/kg of body weight per day. A preferreddosage regimen for optimum results would be from about 0.1 mg to about25 mg/kg of body weight per day, and such dosage units are employed thata total of from about 7 mg to about 1.8 g of the active compound for asubject of about 70 kg of body weight are administered in a 24 hourperiod. This dosage regimen may be adjusted to provide the optimumtherapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation. A decidedpractical advantage is that these active compounds may be administeredin any convenient manner such as by the oral, aerosol, intravenous,intramuscular, or subcutaneous routes.

The active compounds may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or they may beenclosed in hard or soft shell gelatin capsules, or they may becompressed into tablets or they may be incorporated directly with thefood of the diet. For oral therapeutic administration, these activecompounds may be incorporated with excipients and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2% to about 60% of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween about 5 and 200 mg of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills or capsules may be coated with shellac,sugar or both. A syrup or elixir may contain the active compound,sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amounts used.In addition, these active compounds may be incorporated intosustained-release preparations and formulations.

Compositions according to the present invention having the desiredclarity, stability and adaptability for parenteral use are obtained bydissolving from 0.10% to 10.0% by weight of active compound in a vehicleconsisting of a polyhydric aliphatic alcohol or mixtures thereof.Especially satisfactory are glycerin, propylene glycol, and polyethyleneglycols. The polyethylene glycols consist of a mixture of non-volatile,normally liquid, polyethylene glycols which are soluble in both waterand organic liquids and which have molecular weights of from about 200to 1500. Although various mixtures of the aforementioned non-volatilepolyethylene glycols may be employed, it is preferred to use a mixturehaving an average molecular weight of from about 200 to about 400.

In addition to the active compound, the parenteral solutions may alsocontain various preservatives which may be used to prevent bacterial andfungal contamination. The preservatives which may be used for thesepurposes are, for example, myristyl-gamma-picolinium chloride,benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-alpha-glycerolether, methyl and propyl parabens, and thimerosal. As a practicalmatter, it is also convenient to employ antioxidants. Suitableantioxidants include, for example, sodium bisulfite, sodiummetabisulfite, and sodium formaldehyde sulfoxylate. Generally, fromabout 0.05% to about 0.2% concentrations of anti-oxidant are employed.

These compounds may also be administered by inhalation usingconventional Aerosol® formulations.

The invention will be described in greater detail in conjunction withthe following specific examples.

EXAMPLE 1 4-(3-Pyridinyl)-N-[3-(trifluoromethyl)phenyl]-2-pyrimidinamine

A 7.04 g amount of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one (U.S.Pat. No. 4,281,000) and 18.72 g of [3-(trifluoromethyl)phenyl]guanidinecarbonate in 500 ml of n-propanol was heated at reflux temperature for16 hours. The solvent was evaporated to near dryness, then water wasadded and the precipitate which formed was collected by filtration, thenrecrystallized from hexane to give 5.55 g of the desired product, mp170°-171° C.

EXAMPLE 2 N-(4-Methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinamine

A mixture of 14.4 g of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-oneand 16.1 g of 4-methoxyphenyl guanidine carbonate in 200 ml ofisopropanol was heated at reflux for 20 hours. The reaction mixture wascooled, the crude product was collected by filtration and washed withwater. The material was recrystallized from isopropanol to give thedesired product as light yellow crystals, mp 121°-122° C.

EXAMPLE 3 N-(4-Methoxyphenyl)-4-(4-pyridinyl)-2-pyrimidinamine

A 14.4 g amount of 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one (U.S.Pat. No. 4,281,000) and 16.1 g of 4-methoxyphenylguanidine carbonate in200 ml of isopropanol was heated at reflux for 24 hours. The solvent wasevaporated to 1/3 volume, then the mixture was cooled in an ice-bath tocrystallize the crude product. The product was collected by filtrationand washed with water, then with isopropanol. The material wasrecrystallized from isopropanol/ethylene glycol monomethyl ether to give16.7 g of the desired product as yellow crystals, mp 174°-175° C.

EXAMPLE 4 N-(4-Methoxyphenyl)-4-(2-thienyl)-2-pyrimidinamine

A mixture of 10.9 g of 3-dimethylamino-1-(2-thienyl)-2-propen-1-one(U.S. Pat. No. 4,374,988) and 11.8 g of 4-methoxyphenylguanidinecarbonate in 150 ml of isopropanol was heated at reflux for 48 hours.The solution was cooled, then filtered, giving 9.0 g of the desiredproduct as yellow crystals, mp 158°-160° C.

EXAMPLE 5 4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]benzoic acid, methylester

A solution of 10.0 g of 4-guanidinobenzoic acid, hydrochloride in 310 mlof methanol was mixed with 6.0 ml (9.68 g) of thionyl chloride at 0° C.for 15 minutes, then stirred for one hour at room temperature and thenheated at reflux for 16 hours. The solvent was removed in vacuo and thesolid was washed with ether and air dried to give 11.4 g of whitecrystals (A).

The above procedure was repeated using 20.0 g of 4-guanidinobenzoicacid, 11.9 ml (19.4 g) of thionyl chloride and 600 ml of methanol togive 22.6 g of white crystals (B).

The products (A) and (B) were combined and recrystallized from absoluteethanol. The product was washed with cold absolute ethanol and air driedgiving 26.2 g of p-guanidinobenzoic acid, methyl ester, hydrochloride aswhite crystals, mp 137°-138.5° C. (dec.).

A 9.15 g amount of the above compound was partially dissolved in 100 mlof methanol (stored over 4A molecular sieves) and 2.15 g of sodiummethoxide was added. The mixture was stirred briefly, then 7.0 g of3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one was added and the mixturewas heated under argon with stirring for 21.5 hours. The reactionmixture was cooled in an ice bath, then filtered and washed with coldmethanol. The residue was dissolved in a mixture of dichloromethane andmethanol and filtered to remove sodium chloride. The filtrate wasconcentrated on a steam bath until crystal formation. The mixture wasallowed to stand at room temperature for 16 hours then was filtered. Theprecipitate was washed with ice cold methanol then dried and gave 5.8 gof the desired product, mp 194.5°-196.5° C.

EXAMPLE 6 3-Dimethylamino-1-(3-indolyl)-2-propen-1-one

A mixture of 3.18 g of 3-acetylindole and 5.17 ml. (4.36 g) oftert-butoxybis(dimethylamino)methane was heated on a steam bath for 4hours. The cooled reaction mixture was triturated with n-hexanes andgave a semisolid. The solvent was removed in vacuo and the material wastriturated with dichloromethane giving 3.08 g of the desired compound asa tan crystalline solid, mp 239°-245° C.,

EXAMPLE 7 3-Dimethylamino-1-(5-methyl-2-thienyl)-2-propen-1-one

A mixture of 56.08 g of 2-acetyl-5-methylthiophene and 250 ml ofN,N-dimethylformamide dimethylacetal was heated on a steam bath under anair condenser for 16 hours. The mixture was cooled in an ice bath andfiltered giving 66.82 g of the desired compound, mp 118°-121° C.

EXAMPLE 8 3-(Dimethylamino)-1-(5-methyl-2-furanyl)-2-propen-1-one

A mixture of 37.24 g of 2-acetyl-5-methylfuran and 150 ml ofN,N-dimethylformamide dimethylacetal was heated on a steam bath under anair condenser for 16.5 hours. The solvent was removed in vacuo and theresidue taken up in dichloromethane and passed through a short column ofmagnesium silicate. The filtrate was evaporated on a steam bath with theaddition of n-hexanes to a volume of 100-150 ml. Cooling with scratchinggave 28.31 g of the desired compound, mp 123°-125° C.

EXAMPLE 9 3-(Dimethylamino)-1-(1H-pyrrol-2-yl)-(E)-2-propen-1-one

A mixture of 39.6 g of 2-acetylpyrrole and 104 ml (87.7 g) oftert-butoxy bis(dimethylamino)methane was heated on a steam bath for 20minutes. The reaction was allowed to subside, then heating was continuedfor 6 hours. The mixture solidified then was slurried in hexane withchilling. The crude product was collected, washed with hexane and dried.The solid was dissolved in chloroform containing 5% methanol andfiltered through magnesium silicate. The eluent was evaporated in vacuoand the residue was recrystallized from dichloromethane/hexanecontaining a small amount of methanol. The solid was collected, washedwith hexane then dried in vacuo giving 25.1 g of the desired compound asyellow crystals, mp 192°-193° C. (dec.).

The following 3-(dimethylamino)acrylophenone intermediate compoundslisted in Table III were prepared in a similar manner to the proceduresdescribed in Examples 6-8 and by those described in U.S. Pat. Nos.4,281,000, 4,374,988 and in Case No. 29,240, Ser. No. 672,753, filed onNov. 19, 1984.

                  TABLE III                                                       ______________________________________                                        3-(Dimethylamino)acrylophenone Intermediates                                   ##STR5##                                                                      ##STR6##                                                                     Ex.     R.sub.3      R.sub.4  R.sub.5                                                                            MP °C.                              ______________________________________                                        10      2-Furanyl    H        H    84-86                                      11      2-pyridinyl  H        H    127-130                                    12      2-furanyl    CH.sub.3 H    Oil                                        13      4-pyridinyl  CH.sub.3 H    106-108                                    14      4-methyl-3-  H        H    116-118                                            pyridinyl                                                             15      4-methyl-3-  H        CH.sub.3                                                                           119-120                                            pyridinyl                                                             16      2-pyrazinyl  H        H    132-133                                    17      3-thienyl    H        H    89-90                                      18      4-quinolinyl H        H                                               19      3-methyl-2-  H        H    45-49                                              thienyl                                                               20      1-methyl-1 .sub.--H                                                                        H        H    94-95                                              pyrrol-2-yl                                                           21      5-methyl-2-  H        CH.sub.3                                                                           123-126                                            thienyl                                                               22      2,5-dimethyl-                                                                              H        H    91-95                                              3-furanyl                                                             23      2-pyridinyl  H        CH.sub.3                                                                           68-70                                      24      2-thienyl    H        CH.sub.3                                                                           97-99                                      25      4-pyridinyl  H        CH.sub.3                                                                           88-89                                      26      3-pyridinyl  H        CH.sub.3                                                                           62-64                                      27      3-pyridinyl  CH.sub.3 H    76-78                                      28      3-methyl-2-  H        H    97-98                                              pyridinyl                                                             29      2-benzo-     H        H    137.0-138.5                                        furanyl                                                               30      3-pyridinyl  H        H    97-99                                      31      2-pheno-     H        H                                                       thiazine                                                              ______________________________________                                    

EXAMPLES 32-251 4,5,6-Substituted-2-pyrimidinamines

The following 4,5,6-substituted-2-pyridinamine final products listed inTable IV were obtained by reacting a 3-(dimethylamino)acrylophenone fromTable III and an appropriately substituted phenylguanidine base,carbonate, sulfate, nitrate or hydrochloride salt in an insert solventsuch as absolute ethanol, n-propanol, isopropanol, 2-methoxyethanol, orn-butanol and the like, with or without a base such as sodium hydroxide,potassium hydroxide or potassium carbonate and the like by heating atthe reflux temperature for from 6-90 hours, then recovering the productin a conventional manner with recrystallization from solvents such asn-propanol, isopropanol, absolute ethanol and the like.

                                      TABLE IV                                    __________________________________________________________________________    2-Amino-4,5,6-substituted Pyrimidinamines                                        Acrylophenone                                                                         Phenylguanidine                                                    Ex.                                                                              Source  Precursor    Product           MP °C.                       __________________________________________________________________________    32 Ex. 12  Phenylguanidine carbonate                                                                  4-(2-Furanyl)-5-methyl- .sub.--N--phenyl-2-                                                     141-142                                                     pyrimidinamine                                        33 Ex. 3   [3-(Trifluoromethyl)-                                                                      4-(4-Pyridinyl)- .sub.--N--[3-(trifluoro-                                                       198-200                                        phenyl]guanidine carbon-                                                                   methyl)phenyl]-2-pyrimidinamine                                  ate                                                                34 Ex. 1   Phenylguanidine carbonate                                                                   .sub.--N--Phenyl-4-(3-pyridinyl)-2-pyrimi-                                                     147-148                                                     dinamine                                              35 Ex. 1   (4-Acetylphenyl)guanidine                                                                   .sub.--N--(4-Acetylphenyl)-4-(3-pyridinyl)-                                                    181-183                                                     2-pyrimidinamine                                      36 Ex. 1   (4-Fluorophenyl)guanidine                                                                   .sub.--N--(4-Fluorophenyl)-4-(3-pyridinyl)-                                                    167-169                                        carbonate    2-pyrimidinamine                                      37 Ex. 11  (4-Methoxyphenyl)guani-                                                                     .sub.--N(4-Methoxyphenyl)-4-(2-pyridinyl)-                                                     162-164                                        dine carbonate                                                                             2-pyrimidinamine                                      38 Ex. 3   (4-Fluorophenyl)guanidine                                                                   .sub.--N--(4-Fluorophenyl)-4-(4-pyridinyl)-                                                    186-188                                        carbonate    2-pyrimidinamine                                      39 Ex. 1   (4-Bromophenyl)guanidine                                                                    .sub.--N--(4-Bromophenyl)-4-(3-pyridinyl)-                                                     174-175                                        carbonate    2-pyrimidinamine                                      40 Ex. 4   (4-Fluorophenyl)guanidine                                                                   .sub.--N--(4-Fluorophenyl)-4-(2-thienyl)-2-                                                    176-178                                        carbonate    pyrimidinamine                                        41 Ex. 11  [3-(Trifluoromethyl)-                                                                      4-(2-Pyridinyl)-  .sub.--N--[3-(trifluoro-                                                      161-162                                        phenyl]guanidine carbon-                                                                   methyl)phenyl]-2-pyrimidinamine                                  ate                                                                42 Ex. 4   Phenylguanidine carbonate                                                                   .sub.--N--Phenyl-4-(2-thienyl)-2-pyrimidin-                                                    137-139                                                     amine                                                 43 Ex. 1   3-Chloro-4-methylphenyl-                                                                    .sub.--N--(3-Chloro-4-methylphenyl)-4-(3-                                                      140-145                                        guanidine carbonate                                                                        pyridinyl)-2-pyrimidinamine                           44 Ex. 11  3-Methylphenylguanidine                                                                     .sub.--N--(3-Methylphenyl)-4-(2-pyridinyl)-                                                    135-137                                        carbonate    2-pyrimidinamine                                      45 Ex. 3   3-Methylphenylguanidine                                                                     .sub.--N--(3-Methylphenyl)-4-(4-pyridinyl)-                                                    157-159                                        carbonate    2-pyrimidinamine                                      46 Ex. 3   Phenylguanidine carbonate                                                                   .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimi-                                                     153-154                                                     dinamine                                              47 Ex. 1   3-Methylphenylguanidine                                                                     .sub.--N--(3-Methylphenyl)-4-(3-pyridinyl)-                                                    102-103                                        carbonate    2-pyrimidinamine                                      48 Ex. 3   4-Ethylphenylguanidine                                                                      .sub.--N--(4-Ethylphenyl)-4-(4-pyridinyl)-                                                     138-140                                        carbonate    2-pyrimidinamine                                      49 Ex. 13  4-Ethylphenylguanidine                                                                      .sub.--N--(4-Ethylphenyl)-5-methyl-4-(4-                                                       132-133                                        carbonate    pyridinyl)-2-pyrimidinamine                           50 Ex. 3   3,4-Dichlorophenylguani-                                                                    .sub.--N--(3,4-Dichlorophenyl)-4-(4-pyri-                                                      214-216                                        dine carbonate                                                                             dinyl)-2-pyrimidinamine                               51 Ex. 1   4-Ethylphenylguanidine                                                                      .sub.--N--(4-Ethylphenyl)-4-(3-pyridinyl)-                                                     120-122.5                                      carbonate    2-pyrimidinamine                                      52 Ex. 11  4-Ethylphenylguanidine                                                                      .sub.-- N--(4-Ethylphenyl)-4-(2-pyridinyl)-                                                    148.5-149.5                                    carbonate    2-pyrimidinamine                                      53 Ex. 4   3-Methylphenylguanidine                                                                     .sub.--N--(3-Methylphenyl)-4-(2-thienyl)-                                                      112.5-114.5                                    carbonate    2-pyrimidinamine                                      54 Ex. 10  Phenylguanidine carbonate                                                                  4-(2-Furanyl)- .sub.--N--phenyl-2-pyrimidin-                                                    144-145                                                     amine                                                 55 Ex. 10  3-Methylphenylguanidine                                                                    4-(2-Furanyl)- .sub.--N--(3-methylphenyl)-                                                      98-99.5                                        carbonate    2-pyrimidinamine                                      56 Ex. 14  4-Ethylphenylguanidine                                                                      .sub.--N--(4-Ethylphenyl)-4-(6-methyl-3-                                                       154-155                                        carbonate    pyridinyl)-2-pyrimidinamine                           57 Ex. 15  4-Ethylphenylguanidine                                                                      .sub.--N--(4-Ethylphenyl)-6-methyl-4-(6-                                                       118-120                                        carbonate    methyl-3-pyridinyl)-2-pyrimidin-                                              amine                                                 58 Ex. 16  4-Ethylphenylguanidine                                                                      .sub.--N(4-Ethylphenyl)-4-pyrazinyl-2-                                                         157.5-159                                      carbonate    pyrimidinamine                                        59 Ex. 16  3-Methylphenylguanidine                                                                     .sub.--N--(3-Methylphenyl)-4-(4-pyrazinyl)-                                                    112.5-117                                      carbonate    2-pyrimidinamine                                      60 Ex. 3   2-Methylphenylguanidine                                                                     .sub.--N--(2-Methylphenyl)-4-pyrazinyl)-2-                                                     129-130.5                                      carbonate    pyrimidinamine                                        61 Ex. 3   3-Ethylphenylguanidine                                                                      .sub.--N--(3-Ethylphenyl)-4-(4-pyridinyl)-                                                     126-128                                        sulfate      2-pyrimidinamine                                      62 Ex. 3   2,5-Dimethylphenylguani-                                                                    .sub.--N--(2,5-Dimethylphenyl)-4-(4-pyri-                                                      131-134                                        dine carbonate                                                                             dinyl-2-pyrimidinamine                                63 Ex. 3   2,3-Dimethylhenylguani-                                                                     .sub.--N--(2,3-Dimethylphenyl)-4-(4-pyri-                                                      121-123                                        dine carbonate                                                                             dinyl)-2-pyrimidinamine                               64 Ex. 17  3-Methylphenylguanidine                                                                     .sub.--N--(3-Methylphenyl)-4-(3-thienyl)-                                                      104.5-105.5                                    carbonate    2-pyrimidinamine                                      65 Ex. 11  2,5-Dimethylphenylguani-                                                                    .sub.--N--(2,5-Dimethylphenyl)-4-(2-pyri-                                                      139-142                                        dine carbonate                                                                             dinyl)-2-pyrimidinamine                               66 Ex. 3   3,5-Dimethylphenylguani-                                                                    .sub.--N--(3,5-Dimethylphenyl)-4-(4-pyri-                                                      183-185                                        dine carbonate                                                                             dinyl)-2-pyrimidinamine                               67 Ex. 3   1-Naphthylguanidine                                                                         .sub.--N--1-Naphthalenyl-4-(4-pyridinyl)-                                                      174-176                                        nitrate      2-pyrimidinamine                                      68 Ex. 11  3,5-Dimethylphenylguani-                                                                    .sub.--N--(3,5-Dimethylphenyl)-4-(2-                                                           114-119                                        dine hydrochloride                                                                         pyridinyl)-2-pyrimidinamine                           69 Ex. 11  1-Naphthylguanidine                                                                         .sub.--N--1-Naphthalenyl-4-(2-pyridinyl)-                                                      135-138                                        nitrate      2-pyrimidinamine                                      70 Ex. 3   2,4-Dimethylphenylguani-                                                                    .sub.--N--(2,4-Dimethylphenyl)-4-(4-pyri-                                                      116-118                                        dine carbonate                                                                             dinyl)-2-pyrimidinamine                               71 Ex. 3   2,4,6-Trimethylphenyl-                                                                     4-(4-Pyridinyl)- .sub.--N--(2,4,6-trimethyl-                                                    142-144                                        guanidine carbonate                                                                        phenyl)-2-pyrimidinamine                              72 Ex. 10  4-Methoxyphenylguanidine                                                                   4-(2-Furanyl)- .sub.--N--(4-methoxyphenyl)-                                                     155-158.5                                      carbonate    2-pyrimidinamine                                      73 Ex. 10  [3-(Trifluoromethyl)-                                                                      4-(2-Furanyl)- .sub.--N--[3-(trifluorometh-                                                     150-154                                        phenyl]guanidine carbon-                                                                   yl)phenyl]-2-pyrimidinamine                                      ate                                                                74 Ex. 10  4-Fluorophenylguanidine                                                                     .sub.--N--(4-Fluorophenyl)-4-(2-furanyl)-                                                      150-152                                        carbonate    2-pyrimidinamine                                      75 Ex. 11   .sub.--N--Cyclopentylguanidine                                                             .sub.--N--Cyclopentyl-4-(2-pyridinyl)-2-                                                       106-109                                        sulfate      pyrimidinamine                                        76 Ex. 11  3,4-Dimethylphenylguani-                                                                    .sub.--N--(3,4-Dimethylphenyl)-4-(2-pyri-                                                      130-133.5                                      dine carbonate                                                                             dinyl)-2-pyrimidinamine                               77 Ex. 17  4-Methoxyphenylguanidine                                                                    .sub.--N--(4-Methoxyphenyl)-4-(3-thienyl)-                                                     158-160.5                                      carbonate    2-pyrimidinamine                                      78 Ex. 10  3-Ethylphenylguanidine                                                                      .sub.--N--(3-Ethylphenyl)-4-(2-furanyl)-2-                                                     95-98                                          sulfate      pyrimidinamine                                        79 Ex. 6   Phenylguanidine carbonate                                                                  4-(1 .sub.--H--Indol-3-yl)- .sub.--N--phenyl-2-                                                 188-190                                                     pyrimidinamine                                        80 Ex. 3   2-Methoxy-5-methylphenyl-                                                                   .sub.--N--(2-Methoxy-5-methylphenyl)-4-(4-                                                     96-98.5                                        guanidine carbonate                                                                        pyridinyl)-2-pyrimidinamine                           81 Ex. 20  3-Methylphenylguanidine                                                                     .sub.--N--(3-Methylphenyl)-4-(1-methyl-1                                     .sub.--H--        117-120                                        carbonate    pyrrol-2-yl)-2-pyrimidinamine                         82 Ex. 20  4-Ethylphenylguanidine                                                                      .sub.--N--(4-Ethylphenyl)-4-(1-methyl-1 .sub.--H-                            -                 89-91                                          carbonate    pyrrol-2-yl)-2-pyrimidinamine                         83 Ex. 20  Phenylguanidine carbonate                                                                  4-(1-Methyl-1 .sub.--H--pyrrol-2-yl)- .sub.--N--                                                118-120                                                     phenyl-2-pyrimidinamine                               84 Ex. 4   3-Ethylphenylguanidine                                                                      .sub.--N--(3-Ethylphenyl)-4-(2-thienyl)-2-                                                     114-116                                        sulfate      pyrimidinamine                                        85 Ex. 17  3-Ethylphenylguanidine                                                                      .sub.--N--(3-Ethylphenyl)-4-(3-thienyl)-                                                       86-89                                          sulfate      2-pyrimidinamine                                      86 Ex. 6   3-Methylphenylguanidine                                                                    4-(1 .sub.--H--Indol-2-yl)- .sub.--N--(3-methylphe                            n-                164-167                                        carbonate    yl)-2-pyrimidinamine                                  87 Ex. 18  3-Methylphenylguanidine                                                                     .sub.--N--(3-Methylphenyl)-4-(4-quinolin-                                                      196-198                                        carbonate    yl)-2-pyrimidinamine                                  88 Ex. 18  Phenylguanidine carbonate                                                                   .sub.--N--Phenyl-4-(4-quinolinyl)-2-pyrimi-                                                    182-184                                                     dinamine                                              89 Ex. 18  4-Ethylphenylguanidine                                                                      .sub.--N--(4-Ethylphenyl)-4-(4-quinolinyl)-                                                    176-178                                        carbonate    2-pyrimidinamine                                      90 Ex. 10  3,5-Dimethylphenylguani-                                                                    .sub.--N--(3,5-Dimethylphenyl)-4-(2-fur-                                                       126-129                                        dine hydrochloride                                                                         anyl)-2-pyrimidinamine                                91 Ex. 4   3,5-Dimethylphenylguani-                                                                    .sub.--N--(3,5-Dimethylphenyl)-4-(2-thien-                                                     152-155                                        dine hydrochloride                                                                         yl)-2-pyrimidinamine                                  92 Ex. 3    .sub.--N--Methyl- .sub.--N--phenyl-                                                        .sub.--N--Methyl- .sub.--N--phenyl-4-(4-pyridinyl                            )-                105-107                                        guanidine hydrochloride                                                                    2-pyrimidinamine                                      93 Ex. 3   2,4-Difluorophenylguani-                                                                    .sub.--N--(2,4-Difluorophenyl)-4-(4-pyri-                                                      172-174                                        dine hydrochloride                                                                         dinyl)-2-pyrimidinamine                               94 Ex. 1   2,4-Difluorophenylguani-                                                                    .sub.--N--(2,4-Difluorophenyl)-4-(3-pyri-                                                      163- 165                                       dine hydrochloride                                                                         dinyl)-2-pyrimidinamine                               95 Ex. 7   3-Methylphenylguanidine                                                                     .sub.--N--(3-Methylphenyl)-4-(5-methyl-2-                                                      114-116                                        carbonate    thienyl)-2-pyrimidinamine                             96 Ex. 3   2,6-Difluorophenylguani-                                                                    .sub.--N--(2,6-Difluorophenyl)-4-(4-pyri-                                                      174-176                                        dine hydrochloride                                                                         dinyl)-2-pyrimidinamine                               97 Ex. 9   Phenylguanidine carbonate                                                                   .sub.--N--Phenyl-4-(1 .sub.--H--pyrrol-2-yl)-2-                                                154-157                                                     pyrimidinamine                                        98 Ex. 1   4-Tert-butylphenylguani-                                                                    .sub.--N--[4-(1,1-Dimethylethyl)phenyl]-4-                                                     130-133                                        dine sulfate (3-pyridinyl)-2-pyrimidinamine                        99 Ex. 1   2,6-Difluorophenylguani-                                                                    .sub.--N--(2,6-Difluorophenyl)-4-(3-pyri-                                                      163-166                                        dine hydrochloride                                                                         dinyl)-2-pyrimidinamine                               100                                                                              Ex. 7   3,5-Dimethylhenylguani-                                                                     .sub.--N--(3,5-Dimethylphenyl)-4-(5-methyl-                                                    133-135                                        dine hydrochloride                                                                         2-thienyl)-2-pyrimidinamine                           101                                                                              Ex. 7   4-Ethylphenylguanidine                                                                      .sub.--N--(4-Ethylphenyl)-4-(5-methyl-2-                                                       123-125                                        carbonate    thienyl)-2-pyrimidinamine                             102                                                                              Ex. 11  3,4-Dimethylphenylguani-                                                                    .sub.--N--[(3,4-Dimethylphenyl)methyl]-4-                                                      158-160                                        dine hydrochloride                                                                         (2-pyridinyl)-2-pyrimidinamine                        103                                                                              Ex. 7   3,5-Dimethylphenylguani-                                                                    .sub.--N--(3,5-Dimethylphenyl)-4-(3-methyl-                                                    151-155                                        dine hydrochloride                                                                         2-thienyl)-2-pyrimidinamine                           104                                                                              Ex. 9   3-Methylphenylguanidine                                                                     .sub.--N--(3-Methylphenyl)-4-(1 .sub.--H--pyrrol-                            2-                129-130                                        carbonate    yl)-2-pyrimidinamine                                  105                                                                              Ex. 8   3-Methylphenylguanidine                                                                    4-(5-Methyl-2-furanyl)- .sub.--N--(3-meth-                                                      119-121                                        carbonate    ylphenyl)-2-pyrimidinamine                            106                                                                              Ex. 21  Phenylguanidine carbonate                                                                  4-Methyl-6-(5-methyl-2-thienyl)- .sub.--N--                                                     133-135                                                     phenyl-2-pyrimidinamine                               107                                                                              Ex. 3   4-(Dimethylamino)phenyl-                                                                    .sub.--N--[4-(Dimethylamino)phenyl]-4-(4-                                                      164-166                                        guanidine dihydrochloride                                                                  pyridinyl)-2-pyrimidinamine                           108                                                                              Ex. 3   3-Methoxyphenylguanidine                                                                    .sub.--N--(3-Methoxyphenyl)-4-(4-pyri-                                                         159-160                                        hydrochloride                                                                              dinyl)-2-pyrimidinamine                               109                                                                              Ex. 11  3-Methoxyphenylguanidine                                                                    .sub.--N--(3-Methoxyphenyl)-4-(2-pyridin-                                                      110-113                                        hydrochloride                                                                              yl)-2-pyrimidinamine                                  110                                                                              Ex. 11  4-(Dimethylamino)phenyl-                                                                    .sub.--N--[4-(Dimethylamino)phenyl]-4-(2-                                                      171-174                                        guanidine dihydrochloride                                                                  pyridinyl)-2-pyrimidinamine                           111                                                                              Ex. 1   3-Methoxyphenylguanidine                                                                    .sub.--N--(3-Methoxyphenyl)-4-(3-pyridin-                                                      126-127                                        hydrochloride                                                                              yl)-2-pyrimidinamine                                  112                                                                              Ex. 1   3,5-Dimethylphenylguani-                                                                    .sub.--N--(3,5-Dimethylphenyl)-4-(3-pyri-                                                      125-128                                        dine hydrochloride                                                                         dinyl)-2-pyrimidinamine                               113                                                                              Ex. 1   4-(Ethoxycarbonyl)phenyl-                                                                  4-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                             197-202                                        guanidine hydrochloride                                                                    amino]benzoic acid, ethyl ester                       114                                                                              Ex. 1   4-(Dimethylamino)phenyl-                                                                    .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-py                            ridinyl)-         165-166                                        guanidine dihydrochloride                                                                  2-pyrimidinyl]-1,4-benzenediamine                     115                                                                              Ex. 22  Phenylguanidine carbonate                                                                  4-(2,5-Dimethyl-3-furanyl)-  .sub.--N--                                                         116-118                                                     phenyl-2-pyrimidinamine                               116                                                                              Ex. 17  4-Ethylphenylguanidine                                                                      .sub.--N--(4-Ethylphenyl)-4-(3-thienyl)-2-                                                     151-152.5                                      carbonate    pyrimidinamine                                        117                                                                              Ex. 22  3-Methylphenylguanidine                                                                    4-(2,5-Dimethyl-3-furanyl)- .sub.--N--(3-                                                       144-146                                        carbonate    methylphenyl)-2-pyrimidinamine                        118                                                                              Ex. 22  3,5-Dimethylphenylguani-                                                                   4-(2,5-Dimethyl-3-furanyl)- .sub.--N--(3,5-                                                     149-152                                        dine hydrochloride                                                                         dimethylphenyl)-2-pyrimidinamine                      119                                                                              Ex. 22  4-Ethylphenylguanidine                                                                     4-(2,5-Dimethyl-3-furanyl)- .sub.--N--(4-                                                       93-96                                          carbonate    ethylphenyl)-2-pyrimidinamine                         120                                                                              Ex. 1   3-Dimethylaminophenyl-                                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-py                            ridinyl)-2-       123-125                                        guanidine dihydrochloride                                                                  pyrimidinyl]-1,3-benzenediamine                       121                                                                              Ex. 11  3-(Ethoxycarbonyl)phenyl-                                                                  3-[[4-(2-Pyridinyl)-2-pyrimidinyl]-                                                             156-158                                        guanidine hydrochloride                                                                    amino]benzoic acid, ethyl ester                       122                                                                              Ex. 11  3-(Dimethylamino)phenyl-                                                                    .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-py                            ridinyl)-2-       109-111                                        guanidine dihydrochloride                                                                  pyrimidinyl]-1,3-benzenediamine                       123                                                                              Ex. 1   3-(Ethoxycarbonyl)phenyl-                                                                  3-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                             95-103                                         guanidine hydrochloride                                                                    amino]benzoic acid, ethyl ester                       124                                                                              Ex. 10  4-(Dimethylamino)phenyl-                                                                    .sub.--N'--[4-(2-Furanyl)-2-pyrimidinyl]-                                                      166-167                                        guanidine dihydrochloride                                                                   .sub.--N, .sub.--N--dimethyl-1,4-benzenediamine      125                                                                              Ex. 4   4-(Dimethylamino)phenyl-                                                                    .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-th                            ienyl)-2-         174-175                                        guanidine dihydrochloride                                                                  pyrimidinyl]-1,4-benzenediamine                       126                                                                              Ex. 22  4-(Dimethylamino)phenyl-                                                                    .sub.--N'--[4-(2,5-Dimethyl-3-furanyl)-2-                                                      126-129                                        guanidine dihydrochloride                                                                  pyrimidinyl]- .sub.--N, .sub.--N--dimethyl-1,4-                               benzenediamine                                        127                                                                              Ex. 19  4-(Dimethylamino)phenyl-                                                                    .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-me                            thyl-2-           145-148                                        guanidine dihydrochloride                                                                  thienyl)-2-pyrimidinyl]-1,4-                                                  benzenediamine                                        128                                                                              Ex. 3   3-(Dimethylamino)phenyl-                                                                    .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-py                            ridinyl)-2-       165-168                                        guanidine dihydrochloride                                                                  pyrimidinyl]-1,3-benzenediamine                       129                                                                              Ex. 12  3,5-Dimethylphenylguani-                                                                    .sub.--N--(3,5-Dimethylphenyl)-4-(2-fur-                                                       155-158                                        dine         anyl)-5-methyl-2-pyrimidinamine                       130                                                                              Ex. 12  4-(Dimethylamino)phenyl-                                                                    .sub.--N'--[4-(2-Furanyl)-5-methyl-2-                                                          146-148                                        guanidine dihydrochloride                                                                  pyrimidinyl]- .sub.--N, .sub.--N--dimethyl-1,4-                               benzenediamine                                        131                                                                              Ex. 29  4-(Dimethylamino)phenyl-                                                                    .sub.--N'--[4-(2-Benzofuranyl)-2-pyrimi-                                                       175-178                                        guanidine dihydrochloride                                                                  dinyl]- .sub.--N, .sub.--N--dimethyl-1,4-benzene-                             diamine                                               132                                                                              Ex. 11  2-Guanidinobenzimidazole                                                                    .sub.--N--[4-(2-Pyridinyl)-2-pyrimidinyl]-                                                     276-279.5                                                   1 .sub.--H--benzimidazol-2-amine                      132                                                                              Ex. 23  Phenylguanidine carbonate                                                                  4-Methyl- .sub.--N--phenyl-6-(2-pyridinyl)-                                                     94-98                                                       2-pyrimidinamine                                      134                                                                              Ex. 4   3-(Dimethylamino)phenyl-                                                                    .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-th                            ienyl)-2-         118-120                                        guanidine dihydrochloride                                                                  pyrimidinyl]-1,3-benzenediamine                       135                                                                              Ex. 8   3-(Dimethylamino)phenyl-                                                                    .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(5-me                            thyl-2-           126-129                                        quanidine dihydrochloride                                                                  furanyl)-2-pyrimidinyl]-1,3-ben-                                              zenediamine                                           136                                                                              Ex. 22  3-(Dimethylamino)phenyl-                                                                    .sub.--N'--[4-(2,5-Dimethyl-3-furanyl)-2-                                                      153-155                                        guanidine dihydrochloride                                                                  pyrimidinyl]- .sub.--N, .sub.--N--dimethyl-1,3-                               benzenediamine                                        137                                                                              Ex. 3   4-Aminoacetylphenylguani-                                                                   .sub.--N--[4-[[4-(4-Pyridinyl)-2-pyrimidin-                                                    294-296                                        dine hydrochloride                                                                         yl]amino]phenyl]acetamide                             138                                                                              Ex. 3   4-(Diethylamino)phenyl-                                                                     .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(4-pyr                            idinyl)-          126-128                                        guanidine dihydrochloride                                                                  2-pyrimidinyl]-1,4-benzenediamine                     139                                                                              Ex. 1   4-(Diethylamino)phenyl-                                                                     .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(3-pyr                            idinyl)-          100-104                                        guanidine dihydrochloride                                                                  2-pyrimidinyl]-1,4-benzenediamine                     140                                                                              Ex. 17  Phenylguanidine carbonate                                                                   .sub.--N--Phenyl-4-(3-thienyl)-2-pyrimidin-                                                    142-143                                                     amine                                                 141                                                                              Ex. 11  4-Fluorophenylguanidine                                                                     .sub.--N--(4-Fluorophenyl)-4-(2-pyridinyl)-                                                    207-209                                        carbonate    2-pyrimidinamine                                      142                                                                              Ex. 11  4-Chlorophenylguanidine                                                                     .sub.--N--(4-Chlorophenyl)-4-(2-pyridinyl)-                                                    220-222                                        carbonate    2-pyrimidinamine                                      143                                                                              Ex. 3   4-Methylphenylguanidine                                                                     .sub.--N--(4-Methylphenyl)-4-(4-pyridinyl)-                                                    197.5-198.5                                    carbonate    2-pyrimidinamine                                      144                                                                              Ex. 31   .sub.--N--[3-(Trifluoromethyl)-                                                           4-(2-Phenothiazine)- .sub.--N--[3-(tri-                                                         240-243                                        phenyl]guanidine carbon-                                                                   fluoromethyl)phenyl]-2-pyrimidin-                                ate          amine                                                 145                                                                              Ex. 31  4-Methoxyphenylguanidine                                                                    .sub.--N--(4-Methoxyphenyl)-4-(2-pheno-                                                        220-225                                        carbonate    thiazine)-2-pyrimidinamine                            146                                                                              Ex. 31  3,4-Dichlorophenylguani-                                                                    .sub.-- N--(3,4-Dichlorophenyl)-4-(2-pheno-                                                    235-238                                        dine carbonate                                                                             thiazine)-2-pyrimidinamine                            147                                                                              Ex. 11  2,4-Dimethylphenylguani-                                                                    .sub.--N--(2,4-Dimethylphenyl)-4-(2-pyri-                                                      111.5-113.5                                    dine carbonate                                                                             dinyl)-2-pyrimidinamine                               148                                                                              Ex. 3   2-Methoxyphenylguanidine                                                                    .sub.--N--(2-Methoxyphenyl)-4-(4-pyridin-                                                      112-117                                        carbonate    yl)-2-pyrimidinamine                                  149                                                                              Ex. 3   2,5-Dimethoxyphenylguani-                                                                   .sub.--N--(2,5-Dimethoxyphenyl)-4-(4-pyri-                                                     151.5-155.0                                    dine carbonate                                                                             dinyl)-2-pyrimidinamine                               150                                                                              Ex. 11  2-Methoxy-5-methylphenyl-                                                                   .sub.--N--(2-Methoxy-5-methylphenyl)-4-(2-                                                     117-118.5                                      guanidine carbonate                                                                        pyridinyl)-2-pyrimidinamine                           151                                                                              Ex. 3   3,4-Dimethylphenylguani-                                                                    .sub.--N--[(3,4-Dimethylphenyl)methyl]-4-                                                      132-136                                        dine hydrochloride                                                                         (4-pyridinyl)-2-pyrimidinamine                        152                                                                              Ex. 29  3-Methylphenylguanidine                                                                    4-(2-Benzofuranyl)- .sub.--N--(3-methyl-                                                        143-144                                        carbonate    phenyl)-2-pyrimidinamine                              153                                                                              Ex. 3   3,4-Dimethylphenylguani-                                                                    .sub.--N--(3,4-Dimethylphenyl)-4-(4-pyri-                                                      169-171.5                                      dine carbonate                                                                             dinyl)-2-pyrimidinamine                               154                                                                              Ex. 17  4-Fluorophenylguanidine                                                                     .sub.--N--(4-Fluorophenyl)-4-(3-thienyl)-                                                      185-187                                        carbonate    2-pyrimidinamine                                      155                                                                              Ex. 31  Phenylguanidine carbonate                                                                  4-(10 .sub.--H--Phenothiazin-2-yl)- .sub.--N--                                                  218-220                                                     phenyl-2-pyrimidinamine                               156                                                                              Ex. 6   4-Ethylphenylguanidine                                                                      .sub.--N--(4-Ethylphenyl)-4-(1 .sub.--H--indol-3-                                              209-210                                        carbonate    yl)-2-pyrimidinamine                                  157                                                                              Ex. 3   1,1'-Biphenylguanidine                                                                      .sub.--N--[1,1'--Biphenyl]-4-yl-4-(4-pyri-                                                     203-205                                        hydrochloride                                                                              dinyl)-2-pyrimidinamine                               158                                                                              Ex. 3   [4-(1,1-Dimethylethyl)-                                                                     .sub.--N--[4-(1,1-Dimethylethyl)phenyl]-                                                       181-183                                        phenyl]guanidine sulfate                                                                   4-(4-pyridinyl)-2-pyrimidinamine                      159                                                                              Ex. 11   .sub.--N--Methyl- .sub.--N--phenyl-                                                        .sub.--N--Methyl- .sub.--N--phenyl-4-(2-pyridinyl                            )-                88-91                                          guanidine hydrochloride                                                                    2-pyrimidinamine                                      160                                                                              Ex. 9   4-Ethylphenylguanidine                                                                      .sub.--N--(4-Ethylphenyl)-4-(1 .sub.--H--pyrrol-2                            -                 131-133                                        carbonate    yl)-2-pyrimidinamine                                  161                                                                              Ex. 19  Phenylguanidine carbonate                                                                  4-(3-Methyl-2-thienyl)- .sub.--N--phenyl-                                                       137-140                                                     2-pyrimidinamine                                      162                                                                              Ex. 25  4-Dimethylaminophenyl-                                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-methy                            l-6-(4-           153-154                                        guanidine dihydrochloride                                                                  pyridinyl)-2-pyrimidinyl]-1,4-                                                benzenediamine                                        163                                                                              Ex. 26  3,5-Dimethylphenylguani-                                                                    .sub.--N--(3,5-Dimethylphenyl)-4-methyl-6-                                                     136-140                                        dine hydrochloride                                                                         (3-pyridinyl)-2-pyrimidinamine                        164                                                                              Ex. 12   .sub.--N--[3-(Trifluoromethyl)-                                                           4-(2-Furanyl)-5-methyl- .sub.--N--[3-(tri-                                                      169-171                                        phenyl] guanidine carbon-                                                                  fluoromethyl)phenyl]-2-pyrimidin-                                ate          amine                                                 165                                                                              Ex. 23   .sub.--N--(3,5-Dimethylphenyl)-                                                            .sub.--N--(3,5-Dimethylphenyl)-4-methyl-6-                                                     110-112                                        guanidine    (2-pyridinyl)-2-pyrimidinamine                        166                                                                              Ex. 10  2-Guanidinobenzimidazole                                                                    .sub.--N--[4-(2-Furanyl)-2-pyrimidinyl]-                                                       306.5-308                                                   1 .sub.--H--benzimidazol-2-amine                      167                                                                              Ex. 23   .sub.--N--[4-(Dimethylamino)-                                                              .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-methy                            l-6-(2-           145-148                                        phenyl]guanidine dihydro-                                                                  pyridinyl)-2-pyrimidinyl]-1,4-                                   chloride     benzenediamine                                        168                                                                              Ex. 3   4-(1-Imidazolyl)phenyl-                                                                     .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)phenyl]-4                            -                 >320                                           guanidine dihydrochloride                                                                  (4-pyridinyl)-2-pyrimidinamine                        169                                                                              Ex. 30  4-(1-Imidazolyl)phenyl-                                                                     .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)phenyl]-4                            -                 134-174                                        guanidine dihydrochloride                                                                  (3-pyridinyl)-2-pyrimidinamine                                                                  (Dec.)                              170                                                                              Ex. 11   .sub.--N--[4-Diethylamino)phen-                                                            .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(2-pyr                            idinyl)-2-        138-139                                        yl]guanidine dihydro-                                                                      pyrimidinyl]-1,4-benzenediamine                                  chloride                                                           171                                                                              Ex. 11  4-(1-Imidazolyl)phenyl-                                                                     .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)phenyl]-4                            -                 204-206                                        guanidine dihydrochloride                                                                  (2-pyridinyl)-2-pyrimidinamine                        172                                                                              Ex. 10  4-(1-Imidazolyl)phenyl-                                                                    4-(2-Furanyl)- .sub.--N--[4-(1 .sub.--H--imidazol-                            1-                211-212.5                                      guanidine dihydrochloride                                                                  yl)phenyl]-2-pyrimidinamine                           173                                                                              Ex. 12   .sub.--N--[3-Dimethylamino)phen-                                                           .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-fu                            ranyl)-5-         154-156                                        yl]guanidine dihydro-                                                                      methyl-2-pyrimidinyl]-1,3-benzene-                               chloride     diamine                                               174                                                                              Ex. 21   .sub.--N--[3-Dimethylamino)phen-                                                           .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(5-me                            thyl-2-           130-133                                        yl]guanidine dihydro-                                                                      thienyl)-2-pyrimidinyl]-1,3-ben-                                 chloride     zenediamine                                           175                                                                              Ex. 17   .sub.--N--[4-(Dimethylamino)-                                                              .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-th                            ienyl)-2-         173-174                                        phenyl]guanidine dihydro-                                                                  pyrimidinyl]-1,4-benzenediamine                                  chloride                                                           176                                                                              Ex. 13   .sub.--N--[3-(Dimethylamino)-                                                              .sub.--N, .sub.-- N--Dimethyl- .sub.--N'--[4-meth                            yl-6-(4-          200-201                                        phenyl]guanidine                                                                           pyridinyl)-2-pyrimidinyl]-1,3-                                   dihydrochloride                                                                            benzenediamine                                        177                                                                              Ex. 4   4-(1-Imidazolyl)phenyl-                                                                     .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)phenyl]-4                            -                 179-189                                        guanidine hydrochloride                                                                    (2-thienyl)-2-pyrimidinamine                                                                    (Dec.)                              178                                                                              Ex. 19   .sub.--N--(3-Methoxyphenyl)-                                                               .sub.--N--(3-Methoxyphenyl)-4-(3-methyl-2-                                                     120-123                                        guanidine hydrochloride                                                                    thienyl)-2-pyrimidinamine                             179                                                                              Ex. 30   .sub.--N--[4-(Acetylamino)phen-                                                            .sub.--N--[4-[[4-(3-Pyridinyl)-2-pyrimidin-                                                    192-195                                        yl]guanidine hydrochlor-                                                                   yl]amino]phenyl]acetamide                                        ide                                                                180                                                                              Ex. 30   .sub.--N--(4-Benzenesulfonamido)-                                                         4-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                             224-225                                        guanidine hydrochloride                                                                    amino]benzenesulfonamide                              181                                                                              Ex. 3    .sub.--N--(3-Chlorophenyl)guani-                                                           .sub.--N--(3-Chlorophenyl)-4-(4-pyridinyl)-                                                    160-161                                        dine carbonate                                                                             2-pyrimidinamine                                      182                                                                              Ex. 30   .sub.--N--(3-Chlorophenyl)guani-                                                           .sub.--N--(3-Chlorophenyl)-4-(3-pyridinyl)-                                                    146-148                                        dine carbonate                                                                             2-pyrimidinamine                                      183                                                                              Ex. 17   .sub.--N--(3-Methoxyphenyl)-                                                               .sub.--N--(3-Methoxyphenyl)-4-(3-thienyl)-                                                     142-145                                        quanidine hydrochloride                                                                    2-pyrimidinamine                                      184                                                                              Ex. 4    .sub.--N--(3-Methoxyphenyl)-                                                               .sub.--N--(3-Methoxyphenyl)-4-(2-thienyl)-                                                     151-153                                        guanidine hydrochloride                                                                    2-pyrimidinamine                                      185                                                                              Ex. 30   .sub.--N--Methyl- .sub.--N--acetyl-                                                        .sub.--N--Methyl- .sub.--N--[4-[[4-(3-pyridinyl)-                            2-                194-197                                        phenyl-guanidine                                                                           pyrimidinyl]amino]phenyl]acetamide                               hydrochloride                                                      186                                                                              Ex. 3    .sub.--N--Methyl- .sub.--N--acetyl-                                                        .sub.--N--Methyl- .sub.--N--[4-[[4-pyridinyl)-2-                                               233-234                                        phenyl-guanidine                                                                           pyrimidinyl]amino]phenyl]acetamide                               hydrochloride                                                      187                                                                              Ex. 11   .sub.--N--Methyl- .sub.--N--acetyl-                                                        .sub.--N--Methyl- .sub.--N--[4-[[4-(2-pyridinyl)-                            2-                179-181                                        phenyl-guanidine                                                                           pyrimidinyl]amino]phenyl]acetamide                               hydrochloride                                                      188                                                                              Ex. 10   .sub.--N--(3-Methoxyphenyl)-                                                              4-(2-Furanyl)- .sub.--N--(3-methoxyphenyl)-                                                     114-116                                        guanidine hydrochloride                                                                    2-pyrimidinamine                                      189                                                                              Ex. 29   .sub.--N--(3-Methoxyphenyl)-                                                              4-(2-Benzofuranyl)- .sub.--N--(3-methoxy-                                                       137                                            guanidine hydrochloride                                                                    phenyl)-2-pyrimidinamine                              190                                                                              Ex. 9    .sub.--N--(Ethylphenyl)guanidine                                                           .sub.--N--(4-Ethylphenyl)-4-(1-methyl-1 .sub.--H-                            -                 89-91                                          carbonate    pyrrol-2-yl)-2-pyrimidinamine                         191                                                                              Ex. 3    .sub.--N--Acetylphenylguanidine                                                            .sub.--N--[4-[[4-(4-Pyridinyl)-2-pyrimi-                                                       294-296                                        hydrochloride                                                                              dinyl]amino]phenyl]acetamide                          192                                                                              Ex. 10   .sub.--N, .sub.--N--Dimethylphenyl-                                                        .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-fu                            ranyl)-5-         154-156                                        guanidine dihydrochloride                                                                  methyl-2-pyrimidinyl]-1,3-benzene-                                            diamine                                               193                                                                              Ex. 30   .sub.--N--Acetylphenylguanidine                                                            .sub.--N--[4-[[4-(3-Pyridinyl)-2-pyrimidin-                                                    192-195                                        hydrochloride                                                                              yl]amino]phenyl]acetamide                             194                                                                              Ex. 11  Sulfonylaminophenyl-                                                                       4-[[4-(2-Pyridinyl)-2-pyrimidinyl]-                                                             274-277                                        guanidine hydrochloride                                                                    amino]benzenesulfonamide                              195                                                                              Ex. 11   .sub.--N--Acetylphenylguanidine                                                            .sub.--N--[4-[[4-(2-Pyridinyl)-2-pyrimidin-                                                    254-255                                        hydrochloride                                                                              yl]amino]phenyl]acetamide                             196                                                                              Ex. 4   3-Methoxyphenylguanidine                                                                    .sub.--N--(3-Methoxyphenyl)-4-(2-thienyl)-                                                     151-153                                        hydrochloride                                                                              2-pyrimidinamine                                      197                                                                              Ex. 30  4-(4-Methylpiperazin-1-                                                                     .sub.--N--[4-(4-Methyl-1-piperazinyl)-                                                         174-175                                        yl)phenylguanidine                                                                         phenyl]-4-(3-pyridinyl)-2-pyrimi-                                dihydrochloride                                                                            dinamine                                              198                                                                              Ex. 7   3-Methoxyphenylguanidine                                                                    .sub.--N--(3-Methoxyphenyl)-4-(5-methyl-2-                                                     149-151 -  hydrochloride thienyl                                              )-2-pyrimidinamine                  199                                                                              Ex. 11  3-Chlorophenylguanidine                                                                     .sub.--N--(3-Chlorophenyl)-4-(2-pyridinyl)-                                                    164-165                                        hydrochloride                                                                              2-pyrimidinamine                                      200                                                                              Ex. 10  4-(4-Methylpiperazin-1-                                                                    4-(2-Furanyl)- .sub.--N--[4-(4-methyl-1-                                                        193-195                                        yl)phenylguanidine                                                                         piperazinyl)phenyl]-2-pyrimidin-                                 dihydrochloride                                                                            amine                                                 201                                                                              Ex. 4   4-(4-Methylpiperazin-1-                                                                     .sub.--N--[4-(4-Methyl-1-piperazinyl)-                                                         215.5-216.5                                    yl)phenylguanidine                                                                         phenyl]-4-(2-thienyl)-2-pyrimidin-                               dihydrochloride                                                                            amine                                                 202                                                                              Ex. 11  4-(4-Methylpiperazin-1-                                                                     .sub.--N--[4-(4-Methyl-1-piperazinyl)-                                                         192-193                                        yl)phenylguanidine                                                                         phenyl]-4-(2-pyridinyl)-2-pyrimi-                                dihydrochloride                                                                            dinamine                                              203                                                                              Ex. 13  4-(4-Methylpiperazin-1-                                                                     .sub.--N--[4-(4-Methyl-1-piperazinyl)-                                                         207-209                                        yl)phenylguanidine                                                                         phenyl]-4-(4-pyridinyl)-2-                                       dihydrochloride                                                                            pyrimidinamine                                        204                                                                              Ex. 22  3-Methoxyphenylguani-                                                                       .sub.--N--(3-Methoxyphenyl)-4-(2,5-dimeth-                                                     124-125                                        dine hydrochloride                                                                         yl-3-furanyl)-2-pyrimidinamine                        205                                                                              Ex. 13  3-Fluorophenylguani-                                                                        .sub.--N--(3-Fluorophenyl)-4-(4-pyridinyl)-                                                    162                                            dine hydrochloride                                                                         2-pyrimidinamine                                      206                                                                              Ex. 30  3-Fluorophenylguani-                                                                        .sub.--N--(3-Fluorophenyl)-4-(3-pyridinyl)-                                                    147-150                                        dine hydrochloride                                                                         2-pyrimidinamine                                      207                                                                              Ex. 11  3-Fluorophenylguani-                                                                        .sub.--N--(3-Fluorophenyl)-4-(2-pyridinyl)-                                                    162-164                                        dine hydrochloride                                                                         2-pyrimidinamine                                      208                                                                              Ex. 30  4-Acetylphenylguani-                                                                       1-[3-[[4-(3-Pyridinyl)-2-pyrimi-                                                                166-168                                        dine         dinyl]amino]phenyl]ethanone                           209                                                                              Ex. 30  1-(Methylethyl)phenyl-                                                                      .sub.--N--[4-(1-Methylethyl)phenyl]-4-(3-                                                      124-125                                        guanidine hydrochloride                                                                    pyridinyl)-2-pyrimidinamine                           210                                                                              Ex. 30  3-Ethylphenylguanidine                                                                      .sub.--N--(3-Ethylphenyl)-4-(3-pyridinyl)-                                                     80-88                                          hydrochloride                                                                              2-pyrimidinamine                                      211                                                                              Ex. 11  3-Ethylphenylguanidine                                                                      .sub.--N--(3-Ethylphenyl)-4-(2-pyridinyl)-                                                     101-104                                        hydrochloride                                                                              2-pyrimidinamine                                      212                                                                              Ex. 11  3-Benzenesulfonamido-                                                                      3-[[4-(2-Pyridinyl)-2-pyrimidinyl]-                                                             223-225                                        guanidine hydrochloride                                                                    amino]benzenesulfonamide                              213                                                                              Ex. 30  3-Benzenesulfonamido-                                                                      3-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                             278-280                                        guanidine hydrochloride                                                                    amino]benzenesulfonamide                              214                                                                              Ex. 24  4-(1,1-Dimethylethyl)-                                                                      .sub.--N--[4-(1,1-Dimethylethyl)phenyl]-4-                                                     150-154                                        phenylguanidine hydro-                                                                     (2-thienyl)-2-pyrimidinamine                                     chloride                                                           215                                                                              Ex. 10  4-(Diethylamino)phenyl-                                                                     .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(2-fur                            anyl)-2-          132-133                                        guanidine hydrochloride                                                                    pyrimidinyl]-1,4-benzenediamine                       216                                                                              Ex. 13  4-Benzenesulfonamido-                                                                      3-[[4-(4-Pyridinyl)-2-pyrimidinyl]-                                                             262-264                                        guanidine hydrochloride                                                                    amino]benzenesulfonamide                              217                                                                              Ex. 13  4-Acetylaminophenyl-                                                                        .sub.--N--[ 3-[[4-(4-Pyridinyl)-2-pyrimi-                                                      267-270                                        guanidine hydrochloride                                                                    dinyl]amino]phenyl]acetamide                          218                                                                              Ex. 30  4-Acetylaminophenyl-                                                                        .sub.--N--[3-[[-(3-Pyridinyl)-2-pyrimi-                                                        239-241                                        guanidine hydrochloride                                                                    dinyl]amino]phenyl]acetamide                          219                                                                              Ex. 11  3-Acetylaminophenyl-                                                                        .sub.--N--[3-[[4-(2-Pyridinyl)-2-pyrimi-                                                       190-192                                        guanidine hydrochloride                                                                    dinyl]amino]phenyl]acetamide                          220                                                                              Ex. 13  3-(1 .sub.--H--Imidazol-1-yl)-                                                              .sub.--N--[3-(1 .sub.--H--Imidazol-1-yl)phenyl]-4                            -                 232-234                                        phenylguanidine di-                                                                        (4-pyridinyl)-2-pyrimidinamine                                   hydrochloride                                                      221                                                                              Ex. 13  4-Acetylamino-3-methyl-                                                                     .sub.--N--[2-Methyl-4-[[4-(4-pyridinyl)-2-                                                     230-235                                        phenylguanidine hydro-                                                                     pyrimidinyl]amino]phenyl]acetamide                               chloride                                                           222                                                                              Ex. 21  4-Acetylaminophenyl-                                                                        .sub.--N--[4-[[4-(5-Methyl-2-thienyl)-2-                                                       227-230                                        guanidine hydrochloride                                                                    pyrimidinyl]amino]phenyl]acetamide                    223                                                                              Ex. 30  3-[2-(Diethylaminoeth-                                                                      .sub.--N--[3-[2-(Diethylamino)ethoxy]phen-                                                     79-82                                          oxy)phenyl]guanidine                                                                       yl]-4-(3-pyridinyl)-2-pyrimi-                                    dihydrochloride                                                                            dinamine                                              224                                                                              Ex. 30  2-Methoxyphenylguani-                                                                       .sub.--N--(2-Methoxyphenyl)-4-(3-pyridin-                                                      99-101                                         dine carbonate                                                                             yl)-2-pyrimidinamine                                  225                                                                              Ex. 24  4-Acetylaminophenyl-                                                                        .sub.--N-- [4-[[4-(2-Thienyl)-2-pyrimidin-                                                     201-203                                        quanidine hydrochloride                                                                    yl]amino]phenyl]acetamide                             226                                                                              Ex. 30  4-Acetylamino-3-methyl-                                                                     .sub.--N--[2-Methyl-4-[4-(3-pyridinyl)-2-                                                      233-235                                        phenylguanidine hydro-                                                                     pyrimidinyl]phenyl]acetamide                                     chloride                                                           227                                                                              Ex. 29  4-Diethylaminophenyl-                                                                       .sub.--N'--[4-(2-Benzofuranyl)-2-pyrimidin-                                                    134-136                                        guanidine hydrochloride                                                                    yl]- .sub.--N, .sub.--N--diethyl-1,4-benzenediamin                            e                                                     228                                                                              Ex. 12  4-Acetylaminophenyl-                                                                        .sub.--N--[4-[[4-(2-Furanyl)-2-pyrimidin-                                                      230-232                                        guanidine hydrochloride                                                                    yl]amino]phenyl]acetamide                             229                                                                              Ex. 13  4-(Imidazol-1-yl)-3-                                                                        .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)-3-(tri-                                               238-239                                        (trifluoromethyl)phen-                                                                     fluoromethyl)phenyl]-4-(4-pyridin-                               ylguanidine dihydro-                                                                       yl)-2-pyrimidinamine                                             chloride                                                           230                                                                              Ex. 11  4-Acetylamino-3-methyl-                                                                     .sub.--N--[2-Methyl-4-[[4-(2-pyridinyl)-2-                                                     232-234                                        phenylguanidine hydro-                                                                     pyrimidinyl]amino]phenyl]acetamide                               chloride                                                           231                                                                              Ex. 24  3-(1-Imidazolyl)phenyl-                                                                     .sub.--N--[3-(1 .sub.--H--Imidazol-1-yl)phenyl]-4                            -                 137-144                                        guanidine dihydro-                                                                         (3-pyridinyl)-2-pyrimidinamine                                   chloride                                                           232                                                                              Ex. 24  3-(1-Imidazolyl)phenyl-                                                                     .sub.--N--[3-(1 .sub.-- H--Imidazolyl)phenyl]-4-(                            2-                183-184.5                                      guanidine dihydro-                                                                         thienyl)-2-pyrimidinamine                                        chloride                                                           233                                                                              Ex. 10  3-(1-Imidazolyl)phenyl-                                                                    4-(2-Furanyl)- .sub.--N--[3-(1 .sub.--H--imidazol-                            1-                160-168                                        quanidine dihydro-                                                                         yl)phenyl]-2-pyrimidinamine                                      chloride                                                           234                                                                              Ex. 10  3-(Diethylamino)ethoxy-                                                                     .sub.--N--[3-[2-(Diethylamino)ethoxy]phen-                      phenylguanidine dihydro-                                                                   yl]-4-(2-furanyl)-2-pyrimidinamine                               chloride                                                           235                                                                              Ex. 10  3-Methylphenylguanidine                                                                    4-(2-Furanyl)- .sub.--N--(3-methylphenyl)-2-                                                    195-199                                        hydrochloride                                                                              pyrimidinamine, hydrochloride                         236                                                                              Ex. 11  4-(1-Imidazolyl)-3-(tri-                                                                    .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)-3-(tri-                                               216-218                                        fluoromethyl)phenyl-                                                                       fluoromethyl)phenyl]-4-(2-pyridin-                               guanidine dihydro-                                                                         yl)-2-pyrimidinamine                                             chloride                                                           237                                                                              Ex. 24  3-(Diethylamino)ethoxy-                                                                     .sub.--N--[3-[2-(Diethylamino)ethoxy]phen-                      phenylguanidine di-                                                                        yl]-4-(2-thienyl)-2-pyrimidinamine                               hydrochloride                                                      238                                                                              Ex. 10  4-Benzenesulfonamido-                                                                      4-[[4-(2-Furnanyl)-2-pyrimidinyl]-                                                              255-257                                        guanidine hydrochloride                                                                    amino]benzenesulfonamide                              239                                                                              Ex. 21  4-Benzenesulfonamido-                                                                      4-[[4-(5-Methyl-2-thienyl)-2-                                                                   241-245                                        guanidine hydrochloride                                                                    pyrimidinyl]amino]benzenesul-                                                 fonamide                                              240                                                                              Ex. 17   .sub.--N--Methylacetylamino-                                                               .sub.--N--Methyl- .sub.--N--[4-[[                                            4-(3-thienyl)-2-  150-153                                        phenylguanidine hydro-                                                                     pyrimidinyl]amino]phenyl]acetamide                               chloride                                                           241                                                                              Ex. 13  3-[4-Methyl-1-pipera-                                                                       .sub.--N--[3-(4-Methyl-1-piperazinyl)phen-                                                     150-151.5                                      zinyl]phenylguanidine                                                                      yl]-4-(4-pyridinyl)-2-pyrimidina-                                hydrochloride                                                                              mine                                                  242                                                                              Ex. 10  3-[4-Methyl-1-pipera-                                                                      4-(2-Furanyl)- .sub.--N--[3-(4-methyl-1-                                                        134.5-136                                      zinyl]phenylguanidine                                                                      piperazinyl)phenyl]-2-pyrimidina-                                hydrochloride                                                                              mine                                                  243                                                                              Ex. 24  3-[4-Methyl-1-pipera-                                                                       .sub.--N--[3-(4-Methyl-1-piperazinyl)phen-                                                     125-126.5                                      zinyl]phenylguanidine                                                                      yl]-4-(2-thienyl)-2-pyrimidinamine                               hydrochloride                                                      244                                                                              Ex. 13  2-Dimethylaminophenyl-                                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-py                            ridinyl)-2-       114-119                                        guanidine dihydro-                                                                         pyrimidinyl]-1,2-benzenediamine                                  chloride                                                           245                                                                              Ex. 13  3-(Diethylamino)ethoxy-                                                                     .sub.--N--[3-[2-(Diethylamino)ethoxy]phen-                                                     100-103                                        phenylguanidine di-                                                                        yl]-4-(4-pyridinyl)-2-pyrimidina-                                hydrochloride                                                                              mine                                                  246                                                                              Ex. 24  3-(Diethylamino)ethoxy-                                                                     .sub.--N--[4-[2-(Diethylamino)ethoxy]phen-                      phenylguanidine di-                                                                        yl]-4-(2-thienyl)-2-pyrimidinamine                               hydrochloride                                                      247                                                                              Ex. 24  3-(Dimethylamino)ethoxy-                                                                    .sub.--N--[4-[2-(Dimethylamino)ethoxy]phen-                                                    96-98                                          phenylguanidine di-                                                                        yl]-4-(2-thienyl)-2-pyrimidinamine                               hydrochloride                                                      248                                                                              Ex. 17  3-(Dimethylamino)ethoxy-                                                                    .sub.--N--[4-[2-(Dimethylamino)ethoxy]phen-                                                    83-85                                          phenylguanidine di-                                                                        yl]-4-(3-thienyl)-2-pyrimidinamine                               hydrochloride                                                      249                                                                              Ex. 21  4-Diethylaminophenyl-                                                                       .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(5-met                            hyl-2-fur-        118-119                                        guanidine hydrochloride                                                                    anyl)-2-pyrimidinyl]-1,4-benzene-                                             diamine                                               250                                                                              Ex. 21  3-Methoxyphenylguani-                                                                       .sub.--N--(3-Methoxyphenyl)-4-(5-methyl-2-                      dine hydrochloride                                                                         furanyl)-2-pyrimidinamine                             251                                                                              Ex. 13  3-(1H--Imidazol-1-yl)-                                                                     N--[3-(1H--Imidazol-1-yl)phenyl]-4-                                                             232-239                                        phenylguanidine di-                                                (4-pyridinyl)-2-pyrimidinamine                                                           hydrochloride                                                      __________________________________________________________________________

EXAMPLE 252 1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone,oxime

A 2.03 mg portion of N-(4-acetylphenyl)-4-(3-pyridinyl)-2-pyrimidinaminewas mixed with 210 ml of absolute ethanol and 1.26 g of hydroxylaminehydrochloride. An 18.2 ml portion of 1N sodium hydroxide was added, themixture was heated at reflux for 2 hours and then evaporated to 1/4volume. This was cooled, the solid collected, washed with ethanol andwater and dried, giving 1.9 g of the desired product as cream coloredcrystals, mp 239°-241° C.

EXAMPLE 253 1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone,O-methyloxime

The procedure of Example 252 was repeated using methoxyaminehydrochloride, giving 1.78 g of the desired product as yellow crystals,mp 163°-167° C.

EXAMPLE 254N-[1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenyl]ethyl]formamide

A mixture of 7.25 g ofN-(4-acetylphenyl)-4-(3-pyridinyl)-2-pyrimidinamine, 100 ml of formamideand 31 ml, of 98% formic acid was refluxed with stirring overnight. Thesolvents were then boiled off for 1/2 hour, the reaction cooled andpoured into one liter of water. This was extracted with 725 ml ofchloroform. The chloroform extract was back washed with 150 ml of water,then dried, filtered and evaporated to a foam. The foam was partitionedbetween chloroform and water. An equal volume of saturated potassiumbicarbonate was added. The organic phase was separated, dried, filteredand evaporated to a foam. This foam was chromatographed on silica geltopped with a thin layer of hydrous magnesium silicate and eluted withchloroform (first four fractions), then with 2% methanol in chloroform(last two fractions). The sixth (final) fraction was evaporated and thencrystallized from chloroform-hexane, giving 1.05 g of the desiredproduct as cream colored crystals, mp 118°-121° C.

EXAMPLE 255N-[4-[2-(Dimethylamino)ethoxy]phenyl]-4-(3-pyridinyl)-2-pyrimidinamine

A 1.10 g portion of dry 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenolwas dissolved in 25 ml of dimethylformamide. A 213 mg portion of sodiumhydride (50% in oil) was added, the reaction was sealed and stirred for45 minutes. A 480 mg portion of 2-dimethylaminoethyl chloride in 2 ml ofdimethylformamide was added and the sealed mixture was stirredovernight. The solvent was removed at 60° C. and the residue partitionedbetween 25 ml of water and 50 ml of ethyl acetate. The aqueous phase wasextracted twice with ethyl acetate. The organic phases were combined,washed with 1N sodium hydroxide, dried, filtered and evaporated. Theresidue was taken up in 20 ml of chloroform, boiled down to 1/3 volumeand hexane added to turbidity. The mixture was allowed to standovernight, giving 400 mg of the desired product as beige crystals, mp108°-110° C.

EXAMPLE 256 N-[4-[3-(Dimethylamino)propoxy]phenyl]-4-(3-pyridinyl)-2-pyrimidinamine

A 5.46 g portion of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol wasreacted with 3-dimethylaminopropyl chloride by the procedure of Example255, giving 2.9 g of the desired product, mp 85°-87° C.

EXAMPLE 257N-[4-[2-(Diethylamino)ethoxy]phenyl]-4-(4-pyridinyl)-2-pyrimidinamine

The procedure of Example 256 was repeated using4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenol, giving 300 mg of thedesired product as yellow crystals, mp 85°-87° C.

EXAMPLE 258N-[4-[2-(Diethylamino)ethoxy]phenyl]-4-(3-pyridinyl)-2-pyrimidinamine

The procedured of Example 255 was repeated, using 2-diethylaminoethylchloride, giving 3.45 g of the desired product as yellow crystals, mp87°-89° C.

EXAMPLE 259N-[4-[2-(Dimethylamino)ethoxy]phenyl]-4-(4-pyridinyl)-2-pyrimidinamine

The procedure of Example 255 was repeated using4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenol, giving 1.6 g of thedesired product as yellow crystals, mp 120°-122° C.

EXAMPLE 260N-[4-[2-(Dimethylamino)ethoxy]phenyl]-N',N'-dimethyl-N-[4-(4-pyridinyl)-2-pyrimidinyl]-1,2-ethanediamine

The procedure of Example 259 was repeated. Subsequent crops of crystalsgave 0.4 g of the desired product, mp 87°-91° C.

EXAMPLE 261N-[4-[3-(Dimethylamino)propoxy]phenyl]-4-(4-pyridinyl)-2-pyrimidinamine

A 2.78 g portion of 4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenol and2.35 g of 3-dimethylaminopropyl chloride were reacted as described inExample 255, giving 850 mg of the desired product, mp 123°-124.5° C.

EXAMPLE 262 [4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]phenoxy]aceticacid, ethyl ester

A mixture of 5.58 g of 4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenolwas reacted with ethyl bromo acetate as described in Example 255, giving1.8 g of the desired product as yellow crystals, mp 109°-111° C.

EXAMPLE 263N-(4-Methoxyphenyl)-N-methyl-4-(3-pyridinyl)-2-pyrimidinamine

A 2.78 g portion of N-(4-methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinaminewas dissolved in 30 ml of dimethylformamide. A 528 mg portion of sodiumhydride (50% in oil) was added, the reaction sealed and stirred for 45minutes. A solution of 1.70 g of methyl iodide in 2 ml ofdimethylformamide was added, the sealed mixture was stirred overnightand the solvent removed. The residue was partitioned between water andchloroform. The organic phase was dried, filtered and evaporated. Theresidue was crystallized from ether-hexane giving 1.4 g of the desiredproduct as yellow crystals, mp 88°-90° C.

EXAMPLE 264N-(4-Methoxyphenyl)-N-methyl-4-(4-pyridinyl)-2-pyrimidinamine

The procedure of Example 263 was repeated usingN-(4-methoxyphenyl)-4-(4-pyridinyl)-2-pyrimidinamine, giving 510 mg ofthe desired product as yellow crystals, mp 124°-126° C.

EXAMPLE 265N-[2-(Diethylamino)ethyl]-4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide

A 1.55 ml portion of diethylethylenediamine was added to a solution of0.01 mole of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acidchloride in 50 ml of 1,2-dimethoxyethane. A 10 ml portion oftriethylamine was added and the mixture was stirred for 2 hours. Thesolid was collected, washed with water and recrystallized from absoluteethanol, giving 1.22 g of the desired product, mp 148°-150° C.

EXAMPLE 266 N-Methyl-4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide

A 5.85 g portion of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acidin 30 ml of thionyl chloride was refluxed on a steam bath for one hour,then evaporated to dryness. The residue was boiled with dimethoxyethane,then cooled and the solid recovered and washed with ether, giving 6.90 gof 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid chloride.

A 6.03 g portion of the above acid chloride was suspended in 25 ml ofethanol and 10 ml of 25% aqueous methyl amine was added. The resultingsolid was collected, taken up in hot 2-methoxyethanol, cooled and thesolid collected, giving 3.35 g of the desired product, mp 254°-257° C.

EXAMPLE 267 4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]benzoic acid

To a solution of 19.89 g of4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid, ethyl ester in 200ml of 3A ethanol was added 12.5 ml of 10N sodium hydroxide. This mixturewas refluxed on a steam bath for 3 hours and then allowed to evaporate.The residue was taken up in water and treated with 10.4 ml ofconcentrated hydrochloric acid. The resulting solid was collected anddried, giving 18.11 g of the desired product, mp 311°-317° C.

EXAMPLE 268 [4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]phenoxy]acetic acid

An 800 mg portion of[4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenoxy]acetic acid, ethylester was dissolved in 100 ml of ethanol and 10.7 ml of 1N sodiumhydroxide was added. The mixture was stirred for 2 hours, the solventremoved and the residue dissolved in 5 ml of water. The pH was adjustedto 7.0 with 1N hydrochloric acid and the solid collected, washed withwater and dried. The solid was recrystallized fromdimethylformamideethanol, giving 600 mg of the desired product as yellowcrystals, mp 308°-310° C.

EXAMPLE 2694-[2-[(4-Methoxyphenyl)amino]-4-pyrimidinyl]-1-methylpyridinium iodide

A 2.0 g portion of N-(4-methoxyphenyl)-4-(4-pyridinyl-2-pyrimidinaminewas dissolved in 550 ml of absolute ethanol and filtered. To this wasadded 10 ml of iodomethane. The reaction was heated on a steam bath for4 hours. Another 10 ml of iodomethane was added and refluxing wascontinued overnight. The mixture was cooled, the solid collected, washedwith ethanol and dried, giving 2.2 g of the desired product as purplecrystals, mp 282°-284° C.

EXAMPLE 270 4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenol

A 25.0 g portion of N-(4-methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinaminewas dissolved in 200 ml of 48% hydrobromic acid and stirred overnightunder an argon atmosphere. The mixture was then heated on a steam bathfor 7 hours, cooled overnight and evaporated at 60° C. The residue wasbasified with 200 ml of saturated potassium bicarbonate solution andstirred for 1.5 hours. The solid was collected, washed with water, driedand recrystallized from hot absolute ethanol, giving 19.1 g of thedesired product, mp 223°-225° C.

EXAMPLE 271 4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]phenol

The procedure of Example 270 was repeated usingN-(4-methoxyphenyl)-4-(4-pyridinyl)-2-pyrimidinamine, giving 3.0 g ofthe desired product as yellow crystals, mp 268°-270° C.

EXAMPLE 272 N-[4-(2-Propenyloxy)phenyl]-4-(3-pyridinyl)-2-pyrimidinamine

A 2.73 g portion of dry 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenolwas dissolved in 50 ml of dry dimethylformamide. A 528 mg portion ofsodium hydride (50% in oil) was added, the reaction was sealed andstirred for 45 minutes. A solution of 1.33 g of allyl bromide in 10 mlof dimethylformamide was added, the sealed mixture was stirred overnightand then evaporated at 80° C. The residue was partitioned between waterand chloroform. The organic phase was separated, dried and filtered. Thefiltrate was evaporated and the residue crystallized fromchloroform-hexane, giving 1.7 g of the desired product as yellowcrystals, mp 105°-108° C.

EXAMPLE 273 N-(4-Ethylphenyl)-4-(4-pyridinyl)-2-pyrimidinamine,pyridine-1-oxide

A mixture of 2.76 g ofN-(4-ethylphenyl)-4-(4-pyridinyl)-2-pyrimidinamine and 3.45 g ofm-chloroperbenzoic acid in 100 ml of dichloromethane was stirred at roomtemperature for 20 hours. The mixture was washed three times with anaqueous saturated solution of sodium bicarbonate and a small amount ofsaturated saline. The organic layer was dried over magnesium sulfate,filtered through diatomaceous earth, then evaporated in vacuo to give agelatenous solid. The solid was slurried with 50 ml of dichloromethaneand filtered. The solid was washed with a small amount ofdichloromethane and air dried to give 500 mg of the product.Recrystallization from absolute methanol gave 460 mg of the desiredproduct, mp 223°-225° C.

EXAMPLE 274 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, dihydrochloride

A 2.0 g amount of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine wasdissolved in 70 ml of dichloromethane with warming. The solution wascooled to room temperature, then hydrogen chloride gas was bubbled in togive a brick red precipitate. The mixture became very thick and moredichloromethane was added. The precipitate was collected, air dried,then dried in vacuo and gave 2.63 g of the desired product as red-orangecrystals, mp 259°-262° C.

EXAMPLE 275 N-[4-(4-Pyridinyl)-2-pyrimidinyl]-1,4-benzenediamine,hydrochloride

A 2.85 g amount ofN-[4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenyl]acetamide was added toa mixture of 10 ml of concentrated hydrochloric acid and 10 ml of water.The reaction mixture was heated at reflux for 90 minutes, thenevaporated in vacuo to obtain a solid. The solid was recrystallized from3A ethanol/water and gave 2.31 g of the desired product as a yellowcrystalline solid, mp 292°-295° C.

Additional hydrochloride salts listed in Examples 276 to 287 in Table Vwere obtained from the corresponding base compound by followingprocedures similar to those described in Examples 274 and 275 andemploying various other solvents such as isopropyl alcohol, ethanol,ether and the like.

                  TABLE V                                                         ______________________________________                                        Ex   Compound                   MP °C.                                 ______________________________________                                        276  4-(3-Pyridinyl)-N--[3-trifluoromethyl)-                                                                  220-223                                            phenyl]pyrimidinamine, hydrochloride                                     277  N,N,--Dimethyl-N'--[4-(3-pyridinyl)-2-pyrim-                                                             239-245                                            idinyl]-1,4-benzenediamine, trihydrochloride                             278  N--]4-[2-(Diethylamino)ethoxy]phenyl]-4-                                                                 115-150                                            (3-pyridinyl)-2-pyrimidinamine, hydrochlo-                                                               (dec)                                              ride                                                                     279  N,N--Dimethyl-N'--[4-(2-pyridinyl)-2-(pyrimi-                                                            204-213                                            dinyl)]-1,3-benzenediamine, dihydrochloride                              280  N,N--Dimethyl-N'--[4-(2-pyridinyl)-2-pyrimi-                                                             202-205                                            dinyl]-1,3-benzenediamine, trihydrochloride                              281  N,N--Dimethyl-N'--[4-(4-pyridinyl)-2-pyrimi-                                                             178-184                                            dinyl]-1,3-benzenediamine, dihydrochloride                               282  N,N--Dimethyl-N'--[4-(2-pyridinyl)-2-pyrimi-                                                             229-234                                            dinyl]-1,4-benzenediamine, dihydrochloride                               283  N,N--Dimethy-N'--[4-(4-pyridinyl)-2-pyrimi-                                                              232-235                                            dinyl]-1,4-benzenediamine, trihydrochloride                              284  N--[4-(1-Aminoethyl)phenyl]-4-(3-pyridinyl)-                                  2-pyrimidinamine, trihydrochloride                                       285  N--[3-(1H--Imidazol-1-yl)phenyl]-4-(2-pyri-                                                              232.5-234                                          dinyl)-2-pyrimidinamine, hydrochloride                                   286  N--[3-(1H--Imidazol-1-yl)phenyl]-4-(4-pyri-                                                              259-266                                            dinyl)-2-pyrimidinamine, hydrochloride                                   287  4-(2-Furanyl)-N--[3-(4-methyl-1-piperazin-                                                               259-263                                            yl)phenyl]-2-pyrimidinamine, hydrochloride                               ______________________________________                                    

EXAMPLE 288 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, sulfate

A 2.48 g amount of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine wasdissolved in 120 ml of absolute ethanol with heating, then a solution of1.02 g of concentrated sulfuric acid in 25 ml of ethanol was addeddropwise with stirring. The mixture turned orange then a yellowprecipitate formed. The mixture was chilled, the preciptate wascollected, by filtration, washed with cold ethanol then with ether, andair dried to give 2.73 g of yellow-orange crystals.

The preceding compound was dissolved in a small amount of water, then asaturated aqueous solution of sodium bicarbonate was added to pH 8.0 toyield a light yellow precipitate. The precipitate was collected, washedwith water and dried in vacuo. A 2.25 g portion this material wasrecrystallized from about 200 ml of absolute methanol in the cold. Theproduct was collected, washed with absolute ethanol and dried in vacuoto give 1.75 g of the desired product as orange crystals, mp 233°-235°C.

Additional sulfate salts which were prepared from the corresponding basecompound in the manner described hereinabove are listed as Examples 289to 300 in Table VI.

                  TABLE VI                                                        ______________________________________                                        Ex   Compound                   MP °C.                                 ______________________________________                                        289  4-(2-Pyridinyl)-N--[3-trifluoromethyl)-                                                                  208-211                                            phenyl]-2-pyrimidinamine, sulfate                                        290  N--(3-Methylphenyl)-4-(2-thienyl)-2-pyrimi-                                                              207.5-210                                          dinamine, sulfate                                                        291  4-(2-Furanyl)-N--(3-methylphenyl)-2-pyrimi-                                                              187-193                                            dinamine sulfate                                                         292  4-(4-Pyridinyl)-Nj--[3-(trifluoromethyl)phen-                                                            250-253                                            yl)]-2-pyrimidinamine, sulfate                                           293  N--(4-Methoxyphenyl)-4-(3-pyridinyl)-2-                                                                  103-123                                            pyrimidinamine, sulfate                                                  294  N--Phenyl-4-(3-pyridinyl)-2-pyrimidinamine,                                                              167-187                                            sulfate                                                                  295  4-(3-Pyridinyl)-N--[3-trifluoromethyl)phen-                                                              196-199                                            yl]-2-pyrimidinamine, sulfate                                            296  N--(3,5-Dimethylphenyl)-[4-(3-pyridinyl)-2-                                                              209-214                                            pyrimidinamine, sulfate                                                  297  N--(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                               216-218                                            pyrimidinamine, sulfate                                                  298  N--(3,5-Dimethylphenyl)-4-methyl-6-(5-methyl-                                                            232-234                                            2-thienyl)-2-pyrimidinamine, sulfate                                     299  4-(2-Furanyl)-5-methyl-Nj--phenyl-2-pyrimi-                                                              140-144                                            dinamine, sulfate                                                        300  N,N--Dimethyl-N'--[4-(4-pyridinyl)-2-pyrimi-                                                             204-211                                            dinyl]-1,3-benzenediamine, sulfate                                       ______________________________________                                    

EXAMPLE 301 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, phosphate

A 2.0 g amount of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine wasdissolved in 100 ml of ethanol with heating. The solution was allowed tocool to room temperature, then a solution of 2.07 g of phosphoric acidin 25 ml of ethanol was added with stirring. The mixture was chilled forseveral hours, then the precipitate which formed was collected byfiltration, washed twice with cold ethanol and dried in vacuo for 16hours to give 3.43 g of the desired product as orange crystals, mp210.5°-212.5° C.

Additional phosphate salts which were prepared from the correspondingbase compound in the manner described hereinabove are listed as Examples302 to 305 in Table VII.

                  TABLE VII                                                       ______________________________________                                        Ex    Compound                  MP °C.                                 ______________________________________                                        302   N--(3,5-Dimethylphenyl)-4-(3-pyridinyl)-2-                                                              190-192                                             pyrimidinamine, phosphate                                               303   N--(4-Methoxyphenyl)-4-(3-pyridinyl)-2-                                                                 185-188                                             pyrimidinamine, phosphate                                               304   N--Phenyl-4-(3-pyridinyl)-2-pyrimidinamine                                                              176-179                                             phosphate                                                               305   N--(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                              199-202                                             pyrimidinamine, phosphate                                               ______________________________________                                    

EXAMPLE 306 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,(Z)-2-butenedioate (1:1)

A mixture of 4.97 g of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine and2.55 g of maleic acid was dissolved in hot 2-methoxyethanol. Coolinggave 4.15 g of the desired product as an orange crystalline solid, mp211°-214° C.

EXAMPLE 307 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, dinitrate

A 2.0 g amount of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine wasdissolved in 100 ml of ethanol with heating. The solution was allowed tocool to room temperature, then a solution of 1.5 ml of concentratednitric acid in 25 ml of ethanol was added with stirring to give ared-orange precipitate. The mixture was allowed to stand 30 minutes atroom temperature, then was chilled for several hours. The solid wascollected, washed with cold absolute ethanol and air dried to give 2.80g of the desired product as red-orange crystals, mp 167°-169° C. (dec.).

EXAMPLE 308 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, compound with2-hydroxy-1,2,3-propanetricarboxylate (2:1)

A mixture of 4.97 g of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine and4.62 g of citric acid was dissolved in hot absolute ethanol. Coolinggave 6.14 g of the product of the example as a yellow cystalline solid,mp 155°-157° C.

EXAMPLE 309 Oxo[phenyl[4-(4-pytridinyl)-2-pyrimidinyl]amino]acetic acid,ethyl ester

A 4.08 g portion of 2-phenylamino-4-(4-pyridinyl)pyrimidine wasdissolved in 20 ml of dimethylformamide. A 5 g portion of 50% sodiumhydride in oil was added using 10 ml of dimethylformamide as a wash.When bubbling ceased, a solution of 2.23 ml of ethyl oxalyl chloride in10 ml of dimethylformamide was added dropwise. Chloroform and aqueous10% potassium bicarbonate were added. The organic layer was separated,dried, filtered and evaporated giving the desired product.

EXAMPLE 310 N-[4-(2-Pyridinyl)-2-pyrimidinyl]-1,4-benzenediamine,dihydrochloride

A 12.86 g portion ofN-[4-[[4-(2-pyridinyl)-2-pyrimidinyl]amino]phenyl]acetamide in a mixtureof 40 ml of water and 40 ml of concentrated hydrochloric acid wasrefluxed for 30 minutes and then cooled. The solid was collected anddried, giving 10.84 g of the desired product, mp 285°-288° C.

Following the procedure of this Example, and using as starting materialsthe products of the indicated examples, the products of Examples 311-322in Table VIII were derived.

                  TABLE VIII                                                      ______________________________________                                             Start-                                                                        ing                                                                           Mate-                          MP                                        Ex.  rial    Product                °C.                                ______________________________________                                        311  Ex. 185 N--Methyl-N'--[4-(3-pyridinyl)-2-                                                                    164-166                                                pyrimidinyl]-1,4-benzenediamine                                  312  Ex. 187 N--Methyl-N'--[4-(2-pyridinyl)-2-                                                                    110-112                                                pyrimidinyl]-1,4-benzenediamine                                  313  Ex. 218 N--[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                                  279-284                                                1,3-benzenediamine, dihydrochloride                              314  Ex. 217 N--[4-(4-Pyridinyl)-2-pyrimidinyl]-                                                                  199-202                                                1,3-benzenediamine                                               315  Ex. 221 2-Methyl-N--[4-(4-pyridinyl)-2-                                                                      297-304                                                pyrimidinyl]-1,4-benzenediamine,                                              dihydrochloride                                                  316  Ex. 219 N--[4-(2-Pyridinyl)-2-pyrimidinyl]-                                                                  153-156                                                1,3-benzenediamine                                               317  Ex. 182 N--[3-(1-Aminomethyl)phenyl]-4-(3-                                                                   230(dec.)                                              pyridinyl)-2-pyrimidinamine                                      318  Ex. 222 N--[4-(5-Methyl-2-thienyl)-2-pyrimi-                                                                 284-287                                                dinyl]1,4-benzenediamine, dihydro-                                            chloride                                                         319  Ex. 228 N--[4-(2-Furanyl)-2-pyrimidinyl]-1,4-                                                                261-266                                                benzenediamine, dihydrochloride                                  320  Ex. 226 2-Methyl-N--[4-(3-pyridinyl)-2-pyrimi-                                                               176-178                                                dinyl]-1,4-benzenediamine                                        321  Ex. 230 2-Methyl-N--[4-(2-pyridinyl)-2-pyrimi-                                                               196-198                                                dinyl]-1,4-benzenediamine                                        322  Ex. 191 N--[4-(4-Pyridinyl)-2-pyrimidinyl]-                                                                  192-193.5                                              1,4-benzenediamine                                               ______________________________________                                    

EXAMPLE 3232-[1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenyl]ethylidene]hydrazinecarboxamide

A 2.9 g portion of1-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone was mixedwith 1.23 g of semicarbazide hydrochloride in 200 ml of absolute ethanoland 1.10 ml of 10N sodium hydroxide was added. This mixture was refluxedovernight, then cooled to room temperature and the solid collected andwashed with ethanol, water and ethanol. The solid was recrystallizedfrom dimethylsulfoxide/ethanol, giving 2.9 g of the desired product, mp256°-258° C.

EXAMPLE 324N-[4-[2-[bis(1-Methylethyl)amino]ethoxy]phenyl]-4-(3-pyridinyl)-2-pyrimidinamine

A 2.64 g portion of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol wasdissolved in 60 ml of dimethylformamide by warming on a steam bath andthen cooled. A 2.0 g portion of diisopropylaminoethyl chloridehydrochloride was added and dissolved with stirring. A 20 ml portion of5N sodium hydroxide was added dropwise over 5 minutes, then 5 ml ofwater was added and the mixture was stirred for 20 hours. The mixturewas then heated on a steam bath for 30 minutes, allowed to stand 48hours and then evaporated. The residual gum was purified by flash drycolumn chromatography on silica gel eluting fractions 1-3 with methanoland fractions 4-6 with 1% methanol in chloroform. Fractions 4-6 werecombined and evaporated, giving 500 mg of the desired product.

EXAMPLE 325α-Methyl-4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzenemethanol

A 1.45 g portion of1-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone was dissolvedwith stirring in 220 ml of ethanol. A 125 mg portion of sodiumborohydride was added and stirring continued for 3 hours. A 63 mgportion of sodium borohydride was added and stirring continuedovernight. A 2 ml portion of glacial acetic acid was added and themixture evaporated. The solid was triturated with water, dried andrecrystallized from 30 ml of ethanol giving 710 mg of the desiredproduct, mp 145°-147° C.

EXAMPLE 326N-[1-[3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenyl]ethyl]formamide

A mixture of 2.9 g of1-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone, 40 ml offormamide and 13 ml of concentrated formic acid was refluxed for 15hours, then cooled and evaporated. The residue was partitioned betweenunsaturated aqueous potassium bicarbonate and chloroform. The organicphase was separated, dried, filtered and evaporated. The residue waschormatographed on silica gel, eluting 125 ml fractions, fractions 1-4with chloroform and fractions 5-7 with 2% methanol in chloroform.Fractions 5-7 were combined and evaporated, giving 1.25 g of the desiredproduct as a yellow foam.

EXAMPLE 327 2-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenol

A mixture of 35 g ofN-(2-methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinamine in 200 ml of 47%aqueous hydrobromic acid was refluxed for 7 hours and then evaporated.The residue was mixed with saturated aqueous potassium bicarbonate andallowed to stand overnight, then filtered. The filtrate wasconcentrated, giving 3.5 g of the desired compound, mp 166°-169° C.

EXAMPLE 328N-[3-(1H-Imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2-pyrimidinamine

A solution of 250 ml of 2-acetylpyridine and 500 ml ofN,N-dimethylformamide dimethyl acetal was heated on a steam bath for 6hours. After concentrating the reaction solution under vacuum, 1 literof hexane was added to the part crystalline residue. The product wascollected as small crystalline particles which were washed with anadditional liter of hexane. Air drying was followed by drying at 45° C.under vacuum, leaving 350.7 g of3-dimethylamino-1-(2-pyridinyl)-2-propen-1-one.

A mixture of 289.0 g of imidazole, 292 g of potassium carbonate, 3liters of dimethyl sulfoxide, and 300.0 g of 1-fluoro-3-nitrobenzene wasstirred and heated for 25.5 hours between 105°-110° C. Then the reactionwas poured into 6 liters of water and cooled in the refrigerator overthe weekend. The crystalline product was collected and washed with 1liter of water. Air drying gave 357.6 g of solid. The solid was taken upin 2.4 liters of ethyl acetate and the hot solution passed throughhydrous magnesium silicate. After boiling the filtrate down to 1.5liters, it was cooled to give a precipitate which was collected andwashed with 200 ml of ethylacetate, to leave 151.7 g of off-whitecrystals. After evaporating the mother liquor to dryness, the residuewas recrystallized from 350 ml of ethyl acetate to give 59.7 g moreproduct. The mother liquor from the second fraction was evaporated andthe residual material recrystallized twice from ethyl acetate to give30.9 g more product. Total product, 242.3 g of1-(3-nitrophenyl)-1H-imidazole.

In a Parr hydrogenation bottle was placed 75.00 g of1-(3-nitrophenyl)-1H-imidazole, 0.70 g platinum oxide, and 250 ml ofethanol. Shaking of this mixture in a Parr hydrogenation apparatus wascontinued until no more hydrogen was taken up. This process was repeatedwith 76.33 g of the imidazole, 1.0 g of platinum oxide and 250 ml ofethanol and again with 90.4 g of the imidazole, 1.0 g of platinum oxideand 240 ml of ethanol, until a total of 241.63 g had been reduced. Foreach batch the catalyst was filtered off and the solvent was removedunder vacuum; and then the residues were combined to give 207.2 g ofgray crystalline amine. Next the amine was recrystallized from 530 ml of2-propanol. After collecting the product, it was washed with 200 ml of2-propanol, and dried, under vacuum, to give 156.4 g of3-(1H-imidazol-1-yl)benzamine.

A solution of 43.3 g of hydrogen chloride in 290 ml of ethanol was addedto 189.0 g of 3-(1H-imidazol-1-yl)benzamine in a 2 liter Erlenmeyerflask. Then 104.7 g of cyanamid was added. The mixture was cautiouslywarmed in a water bath to an internal temperature of 83° C. over 25minutes. When no exotherm had been noted, the flask was placed insidethe steam bath and heated for 2 hours. A final temperature of 97° C. wasachieved. The resulting brown syrup which was[3-(1H-imidazol-1-yl)phenyl]guanidine, monohydrochloride, was used inthe next reaction without further purification.

A mixture of 164 g of ppotassium carbonate, 209.1 g of3-dimethylamino-1-(2-pyridyl)-2-propen-1-one, 1.187 mole of crude[3-(1H-imidazol-1-yl)phenyl]guanidine monohydrochloride, and 1 liter ofmethoxyethanol was stirred and heated under very gentle reflux. Adry-ice condenser filled with water was used to prevent plugging by thedimethylammonium carbonate which is given off by the reaction. Thereaction was stopped after 26.5 hours and permitted to stand overnight.A heavy precipitate had formed which was collected as A and washed with100 ml of ether. The filtrate was concentrated under vacuum as B. Both Aand B were triturated with 1.5 liters of water. Then A was washed with300-400 ml of ethanol, followed by 100 ml of ether to leave, on drying,172.9 g of gray solid, mp 200°-202° C. Recrystallization of B from 150ml of 2-propanol gave a black solid, C. Next, a classical fractionalrecrystallization was carried out using methoxyethanol as the solvent.In the final stages, a large amount of charcoal was added to removecolor. In this fashion two main fractions were obtained D, 79.0 g ofyellow crystals, mp 204.5°-205.5° C., and E, 18.05 g of yellow crystals,mp 204°-204.5° C. The yield of D plus E was 26% of the desired product.

EXAMPLE 329 1-(2-Chloroethoxy)-3-nitrobenzene

A mixture of 6.96 g. of m-nitrophenol, 100 ml. of 2-butanone, 6.9 g. ofpotassium carbonate, and 11.74 g. of 2 chloroethyl-tosylate was stirredand heated under reflux for 24 hours. After cooling to room temperature,the salts were filtered off and the filtrate concentrated under vacuum.The residue crystallized on seeding and was recrystallized from carbontetrachloride to give 8.3 g. of product, m.p. 54.5°-57° C.

EXAMPLE 330 1-[2-(3-Nitrophenoxy)ethyl]-1H-imidazole

After dissolving 3.74 g. of imidazole in 60 ml. of dryN,N-dimethylformamide, 1.78 g. of 50% sodium hydride in oil was added.When the effervescence had stopped (circa 1 hr.), 7.35 g. of1-(2-chloroethoxy)-3-nitrobenzene was added. After stirring overnight,the reaction was concentrated under vacuum. Water was added to theresidue and the product was extracted into chloroform. The product wasextracted out of the chloroform layer with dilute hydrochloric acid.Next, the aqueous acid layer was neutralized with potassium carbonateand the oily product extracted into chloroform. Upon drying thechloroform extract with sodium sulfate, it was concentrated under vacuumto an oil which crystallized on standing. Recrystallization fromisopropyl acetate gave 6.12 g. of product as the monohydrate, m.p.52.5°-55.5° C.

EXAMPLE 331 3-[2-(1H-Imidazol-1-yl)ethoxy]benzamine

Using a Parr hydrogenator, 5.00 g. of1-[2-(3-nitrophenoxy)ethyl]-1H-imidozole in 100 ml. of ethanol and 0.2g. of platinum oxide was hydrogenated until the hydrogen uptake stopped.The catalyst was filtered off and the filtrate concentrated undervacuum. Several recrystallizations from isopropyl acetate gave 2.8 g. ofamine, m.p. 74°-76.5° C.

EXAMPLE 332 [3-[2-(1H-Imidazol-1-yl)ethoxy]phenyl]-guanidineDihydrochloride

To a solution of 1.7 g. of hydrogen chloride in 50 ml. of ethanol wasadded 4.70 g. of 3-[2-(1H-imidazol-1-yl)ethoxy]benzamine in 10 ml. ofethanol. After concentration under vacuum a foam was obtained whichgradually crystallized. Next 1.95 g. of cyanamid and 20 ml. of ethanolwere added and the mixture heated cautiously, first in a water bath,then directly in a steam bath for a total of 5 hours. A light brown oilyguanidine resulted, which was used without purification.

EXAMPLE 333 3-[2-(4-Morpholinyl)ethoxy]-benzenamine

N-[2-Chloroethyl)morpholine hydrochloride, 80 g., was partitionedbetween 5N sodium hydroxide and methylene chloride. After drying theorganic layer over magnesium sulfate, the solvent was removed underreduced pressure to leave 65 g. of free amine.

To 36.01 g. of m-aminophenol dissolved in 325 ml. ofN,N-dimethylformamide, 16.3 g. of 50% sodium hydride in oil was added.The reaction was stirred for 1 hour, until the effervescence stopped;then 57 g. of N-(2-chloroethyl)morpholine, from above, was added. Afterstirring overnight, the mixture was heated on a steam bath for 1/2 hr.,then concentrated under vacuum. The residue was taken up in 300 ml. of2N hydrochloric acid and washed twice with ether. After basifying with10N sodium hydroxide, the product was extracted into ether, dried(magnesium sulfate), filtered through hydrous magnesium silicate andevaporated to a brown oil. Distillation gave 34.0 g. of a golden oil,b.p. 165°-180° C./0.45 mm.

EXAMPLE 334 [3-[2-(4-Morpholinyl)ethoxy]phenyl]guanidinemonohydrochloride

Prepared from 3-[2-(4-morpholinyl)ethoxy]-benzamine by the method ofExample 332

EXAMPLE 335 1-(Bromoacetyl)-4-methylpiperazine monohydrochloride

A solution of 10.0 g. of 1-methyepiperazine in 150 ml of chloroform wascooled in a water bath while 17.3 g. of bromoacetyl chloride in 150 ml.of chloroform was added dropwise, with stirring, over 1/2 hour. Acalcium chloride tube protected the reaction from moisture. Afterstirring overnight, the precipitate was collected and washed withchloroform. The crude product was dried under vacuum at 50° and used assuch.

EXAMPLE 336 1-[(4-Aminophenoxy)acetyl]-4-methylpiperazine

Prepared from p-aminophenol and 1-(bromoacetyl)-4-methylpiperazine bythe method of Example 333 to give a product of m.p. 71°-73° C.

EXAMPLE 3371-[[4-[(Aminoiminomethyl)amino]phenoxy]acetyl]-4-methylpiperazineDihydrochloride

Prepared from 1-[(4-aminophenoxy)acetyl]-4-methylpiperazine by themethod of Example 332.

                  TABLE IX                                                        ______________________________________                                             Acryloyl Phenylguanidine           MP                                    Ex.  Source   precurser     Product     °C.                            ______________________________________                                        338  Ex. 11   [3-[2-(1H-Imidazol                                                                          N--[3-[2-(1H-                                                                             149-                                  1-yl)-ethoxy]-                                                                Imidazol-1-yl)-                                                                    151.5                                                                                  phenyl]guanidine                                                                            ethoxy]phenyl-                                                  dihydrochloride                                                 4-(2-pyridinyl)                                                               2-pyrimidinamine                                                              339  Ex. 13   [3-[-(4-morpho-                                                                             N--[3-[2-(4-mor-                                                                          179-                                                linyl)-ethoxy]-                                                                             pholinyl)-  181                                                 phenyl]guanidine                                                                            ethoxy]phenyl]-                                                 monohydrochloride                                               4-(4-pyridinyl)-                                                              2-pyrimidinamine                                                              340  Ex. 24   [3-[2-(4-morpho-                                                                            N--[3-[2-(4-mor-                                                                          134-                                                linyl)ethoxy]-                                                                              pholinyl)ethoxy]-                                                                         136                                                 phenyl]guanidine                                                                            phenyl]-4-(2-                                                   monohydrochloride                                                                           thienyl)-2-pyri-                                                              midinamine                                        341  Ex. 10   [3-[2-(4-morpho-                                                                            4-(2-furanyl)-N--                                                                         88-                                                 linyl)ethoxy]-                                                                              [3-[2-(4-morpho-                                                                          90                                                  phenyl]guanidine                                                                            linyl)ethoxy]-                                                  monohydrochloride                                                                           phenyl]-2-pyri-                                                               midinamine                                        342  Ex. 24   1-[[4-[(Aminoi-                                                                             1-Methyl-4-[[4-                                                                           173-                                                minomethyl)amino]-                                              (2-thienyl)-2-                                                                     175                                                                                    phenoxy]acetyl]-4-                                                                          pyrimidinyl]-                                                   methyl piperazine                                                                           phenoxy]acetyl)-                                                dihydrochloride                                                                             piperazine                                        343  Ex. 24   (4-chlorophenyl)                                                                            N--(4-chlorophenyl)                                                                       185-                                                guanidine carbonate                                             4-(2-thienyl)-2-                                                                   186                                                                                                  pyrimidinamine                                    344  Ex. 26   [2-[bis(1-methyl-                                                                           N--[2-[2-[bis(1-                                                                          54-                                                 ethyl)amino[ethoxy                                              methylethyl)                                                                       57                                                                                     [guanidine hydro-                                                                           amino]ethoxy]                                                   chloride      phenyl]-4-(3-pyri-                                                            dinyl)-2-pyrimidi-                                                            namine                                            ______________________________________                                    

The disease diabetes mellitus is characterized by metabolic defects inthe production and utilization of glucose which results in the failureto maintain appropriate blood sugar levels. The result of this defect iselevated blood glucose or hyperglycemia. Research on the treatment ofdiabetes has centered on attempts to normalize fasting and postprandialblood glucose levels. Treatments have included parenteral administrationof exogenous insulin, oral administration of drugs and dietarytherapies.

Two major forms of diabetes mellitus are now recognized. Type Idiabetes, or insulin-dependent diabetes, is a result of an absolutedeficiency of insulin, the hormone which regulates glucose utilization.Type II diabetes, or insulin-independent diabetes, often occurs in theface of normal, or even elevated, levels of insulin and appears to bethe result of the inability of tissues to respond appropriately toinsulin.

The compounds of the present invention and the pharmacologically activeacid-addition salts thereof, effectively lower blood glucose levels whenadministered orally to genetic strains of hyperglycemic mice which areanimal models of type II diabetes. The exact mechanism by which they actis not known and the invention should not be construed as limited to anyparticular mechanism of action. As effective hypoglycemic agents, thesecompounds are useful for the treatment of hyperglycemia in type IIdiabetes.

The compounds of this invention were tested for hypoglycemic activityaccording to the following procedure.

Obese mice [C57 B1/6J (ob/ob)], their lean littermates (ob/± or +/+) anddiabetic mice [C57 B1/Ks (db/db)] and their non-diabetic littermates(db/+ or +/+) were obtained from Jackson Laboratories, Bar Harbor,Maine. Obese mice were 8 weeks of age and diabetic mice were 9 weeks ofage at the start of the test.

The test compounds were dissolved in methanol, mixed with powderedPurina rodent chow on a weight of compound to weight of chow basis andthoroughly dried.

Groups of 4 control mice received vehicle (methanol) treated chow.

Groups of 4 test mice were fed ad libitum for one month and foodconsumption was measured daily (on week days) by weighing the food binsbefore and after the addition of fresh chow. Thus a 40 g mouse fed thetest compound at a concentration of 0.02% of the diet would receive adose of 20 mg/kg/day if it ate 4 g of chow per day.

Blood samples were collected before the first treatment and once at theend of each week of treatment by retro-orbital puncture using the end ofeach week of treatment by retro-orbital puncture using heparinizedcapillary tubes. Plasma was separated by centrifugation in a Beckmanmicrofuge for 5 minutes. Plasma glucose concentrations were determinedwith the Beckman Glucose Analyzer which uses a glucose oxidase method.

The results of this test on representative compounds of this inventionappear in Table X.

                                      TABLE X                                     __________________________________________________________________________    Effect of Test Compounds on Blood Glucose                                                      Type                                                                              Dose                                                                              Blood Glucose Levels in mg/100 ml                                     of  %   Days                                                 COMPOUND         Mice                                                                              (W/W)                                                                             0  5  7  14 21 28                                    __________________________________________________________________________    N--(4-methylphenyl)-4-(4-                                                                      ob/ob                                                                             0.1 219                                                                              137                                               pyridinyl)-2-pyrimidinamine                                                                    ob/ob                                                                             0.1 210   118                                                                              80                                                           ob/ob                                                                             0.025                                                                             209   223                                                                              166                                         N--(4-Chlorophenyl)-4-(2-                                                                      ob/ob                                                                             0.1 212                                                                              160                                               thienyl)-2-pyrimidinanine                                                                      ob/ob                                                                             0.025                                                                             220   148                                                                              134                                         N--(4-ethylphenyl)-4-(4-                                                                       ob/ob                                                                             0.1 216                                                                              181                                               pyridinyl)-2-pyrimidinamine                                                                    ob/ob                                                                             0.1 223                                                                              164                                               4-(2-furanyl)-N'phenyl-2-                                                                      ob/ob                                                                             0.1 214                                                                              166                                               pyrimidinamine                                                                N--[4-(1,1-Dimethylethyl)                                                                      ob/ob                                                                             0.1 208                                                                              114                                                                              175                                            phenyl]-4-(4-pyridinyl)-2-                                                                     ob/ob                                                                             0.1 214                                                                              169                                                                              155                                            pyrimidinamine   ob/ob                                                                             0.1 218                                                                              124                                                                ob/ob                                                                             0.1 229                                                                              118                                                                ob/ob                                                                             0.1 225   120                                                                              116                                                                              131                                                                              135                                                    ob/ob                                                                             0.05                                                                              214   139                                                                              143                                                                              180                                                                              188                                                    ob/ob                                                                             0.01                                                                              214   163                                                                              138                                                                              181                                                                              162                                                    db/db                                                                             0.1 426   390                                                                              174                                                                              281                                                                              207                                                    db/db                                                                             0.05                                                                              429   314                                                                              293                                                                              250                                                                              270                                                    db/db                                                                             0.01                                                                              431   335                                                                              407                                                                              400                                                                              499                                   N--[4-(Dimethylamino)phenyl]                                                                   ob/ob                                                                             0.1 240                                                                              138                                               4-(4-pyridinyl)-2-                                                                             ob/ob                                                                             0.1 230                                                                              147                                               pyrimidinamine                                                                N--[4-[3-Dimethylamino)propoxy]                                                                ob/ob                                                                             0.1 215                                                                              234                                               phenyl]-4-(3-pyridinyl)                                                       2-pyrimidinamine                                                              N--[4-[2-(Diethylamino)ethoxy]                                                                 ob/ob                                                                             0.1 220                                                                              191                                               phenyl]-4-(3-pyridinyl)-2-                                                    pyrimidinamine                                                                N'--[4-(2-Benzofurnayl)-2-                                                                     ob/ob                                                                             0.1 229                                                                              153                                               pyrimidinyl)-N,N--dimethyl-                                                                    ob/ob                                                                             0.1 202                                                                              147                                               1,4-benzenediamine                                                                             ob/ob                                                                             0.1 223                                                                              144                                               N--[4-[2-(Dimethylam-                                                                          ob/ob                                                                             0.1 218                                                                              151                                                                              167                                            ino)ethoxy]phenyl]-4-                                                                          ob/ob                                                                             0.1 228                                                                              144                                               (4-pyridinyl)-2- ob/ob                                                                             0.1 225                                                                              134                                               pyrimidinamine   ob/ob                                                                             0.1 232   148                                                                              128                                                                              155                                                                              140                                                    ob/ob                                                                             0.05                                                                              230   158                                                                              198                                                                              196                                                                              163                                                    ob/ob                                                                             0.01                                                                              236   163                                                                              252                                                                              175                                                                              177                                                    db/db                                                                             0.1 369   410                                                                              403                                                                              328                                                                              222                                                    db/db                                                                             0.05                                                                              400   277                                                                              404                                                                              329                                                                              250                                                    db/db                                                                             0.01                                                                              368   393                                                                              321                                                                              494                                                                              336                                   N--[4-(1H--Imidazol-1-                                                                         db/db                                                                             0.1 424   397                                                                              233                                         yl)phenyl]4-(4-pyri-                                                                           ob/ob                                                                             0.1 219                                                                              128                                               dinyl)-2-pyrimidin-                                                                            ob/ob                                                                             0.025                                                                             210   200                                                                              148                                         amine            ob/ob                                                                             0.1 211   105                                                                              140                                                          ob/ob                                                                             0.1 222   119                                                                              132                                                          ob/ob                                                                             0.01                                                                              219   158                                                                              159                                                          ob/ob                                                                             0.025                                                                             222   157                                                                              175                                         N,N--Diethyl-N.sup.1 --[4-                                                                     ob/ob                                                                             0.1 223                                                                              138                                               (3-pyridinyl)-2-pyrim-                                                                         ob/ob                                                                             0.1 210                                                                              163                                               idinyl]-1,4-benzene-                                                                           ob/ob                                                                             0.1 216                                                                              153                                               diamine                                                                       N--[4-(1H--Imidazol-                                                                           ob/ob                                                                             0.1 225                                                                              128                                               1-yl)phenyl]-4-(3-                                                                             ob/ob                                                                             0.025                                                                             208   159                                                                              171                                         pyridinyl)-2-pyrim-                                                                            ob/ob                                                                             0.1 218   127                                                                              131                                         idinamine                                                                     N--[4-(1H--Imidazol-                                                                           ob/ob                                                                             0.1 217                                                                              171                                               1-yl)phenyl]-4-(2-                                                                             ob/ob                                                                             0.1 223                                                                              167                                               pyridinyl)-2-pyrimid-                                                                          ob/ob                                                                             0.1 234                                                                              141                                               inamine                                                                       4-(2-Furnayl)-N--[4-                                                                           ob/ob                                                                             0.1 227                                                                              137                                               (1H--imidazol-1-yl)                                                                            ob/ob                                                                             0.025                                                                             215   164                                                                              244                                         phenyl]-2-pyrimidin-                                                                           ob/ob                                                                             0.1 214   140                                                                              160                                         amine                                                                         N--[4-(1H--Imidazol-                                                                           ob/ob                                                                             0.1 221   109                                                                              116                                         1-yl)phenyl]-4-(2-                                                                             ob/ob                                                                             0.025                                                                             221   147                                                                              171                                         thienyl)-2-pyrimid-                                                                            ob/ob                                                                             0.01                                                                              217   212                                                                              161                                         inamine          ob/ob                                                                             0.1 224                                                                              125                                                                ob/ob                                                                             0.1 203                                                                              131                                                                ob/ob                                                                             0.1 231                                                                              126                                                                ob/ob                                                                             0.1 218                                                                              134                                                                ob/ob                                                                             0.025                                                                             218   175                                                                              185                                                          ob/ob                                                                             0.1 220   135                                                                              117                                                          db/db                                                                             0.1 423   492                                                                              349                                         4-[[4-(3-Pyridinyl)-                                                                           ob/ob                                                                             0.1 219                                                                              122                                               2-pyrimidinyl]amino]                                                                           ob/ob                                                                             0.1 240                                                                              147                                               benzenesulfonamide                                                                             ob/ob                                                                             0.1 216                                                                              185                                                                ob/ob                                                                             0.1 229                                                                              142                                                                ob/ob                                                                             0.1 228                                                                              211                                               N--(3-Chlorophenyl)-4                                                                          ob/ob                                                                             0.1 220                                                                              127                                               (4-pyrindinyl)-2-                                                                              ob/ob                                                                             0.1 237                                                                              163                                               pyrimidinamine   ob/ob                                                                             0.1 216                                                                              135                                                                ob/ob                                                                             0.1 205                                                                              157                                                                ob/ob                                                                             0.025                                                                             210   157                                                                              135                                                          ob/ob                                                                             0.1 212   173                                                                              129                                         N--(3-Chlorophenyl)-                                                                           ob/ob                                                                             0.1 205                                                                              135                                               4-(3-pyridinyl)-2-                                                                             ob/ob                                                                             0.025                                                                             221   205                                                                              131                                         pyrimidinamine   ob/ob                                                                             0.1 244   211                                                                              138                                         N--[4-(4-Methyl-l-                                                                             ob/ob                                                                             0.1 212                                                                              236                                               piperazinyl)phenyl]                                                           4-(3-pyridinyl)-2-                                                            pyrimidinamine                                                                N--(3-Chlorophenyl)-                                                                           ob/ob                                                                             0.1 207                                                                              204                                               4-(2-pyridinyl)-2-                                                            pyrimidinamine                                                                4-(2-Furnayl)-N--[4-                                                                           ob/ob                                                                             0.1 203                                                                              149                                               (4-methyl-1-piper-                                                                             ob/ob                                                                             0.025                                                                             210   179                                                                              130                                         azinyl)phenyl]-2-                                                                              ob/ob                                                                             0.1 229   163                                                                              141                                         pyrimidinamine                                                                4-(2-Furanyl)-N--                                                                              ob/ob                                                                             0.1 221                                                                              132                                               (3-methoxyphenyl)                                                                              ob/ob                                                                             0.1 239                                                                              113                                               2-pyrimidinamine ob/ob                                                                             0.1 217                                                                              162                                                                ob/ob                                                                             0.1 219                                                                              209                                               N--[4-(4-Methyl-l-                                                                             ob/ob                                                                             0.1 203                                                                              188                                               piperazinyl)phenyl]                                                           4-(2-thienyl)-2-                                                              pyrimidinamine                                                                N--[4-(4-Methyl- ob/ob                                                                             0.1 204                                                                              210                                               l-piperazinyl)phenyl]                                                         4-(2-pyridinyl)-2-                                                            pyrimidinamine                                                                N--[4-(4-Methyl- ob/ob                                                                             0.1 204   118                                                                              124                                                                              178                                                                              161                                   l-piperazinyl)phenyl]                                                                          ob/ob                                                                             0.025                                                                             210   157                                                                              200                                                                              152                                                                              202                                   4-(4-pyridinyl)-2-                                                                             ob/ob                                                                             0.01                                                                              210   130                                                                              192                                                                              178                                                                              147                                   pyrimidinamine   db/db                                                                             0.1 406   273                                                                              140                                                                              178                                                                              279                                                    ob/ob                                                                             0.1 221                                                                              125                                                                ob/ob                                                                             0.1 233                                                                              131                                                                ob/ob                                                                             0.1 226                                                                              117                                                                ob/ob                                                                             0.1 215                                                                              138                                                                ob/ob                                                                             0.025                                                                             231   154                                                                              134                                                          ob/ob                                                                             0.1 223   171                                                                              137                                         N--[3-(1H--Imidazol-                                                                           ob/ob                                                                             0.1 225                                                                              173                                               l-yl)phenyl]-4-                                                               (3-pyridinyl)-2-                                                              pyrimidinamine                                                                N--[4-[2-(Diethylamino)                                                                        ob/ob                                                                             0.1 228                                                                              154                                               ethoxy]phenyl]-4-(2-                                                                           ob/ob                                                                             0.1 215                                                                              137                                               thienyl)-2-pyrimidinamine                                                     N--[2-[2-[ Bis(1-methyl-                                                                       ob/ob                                                                             0.1 228                                                                              153                                               ethyl)amino]ethoxy]                                                           phenyl]-4-(3-                                                                 inamine                                                                       __________________________________________________________________________

We claim:
 1. A method of treating asthma and allergic diseases in amammal which comprises administering to said mammal an effective amountof a compound selected from the group consisting of those of theformula: ##STR7## wherein R₁ is hydrogen, alkyl(C₁ -C₃), --COCO₂ C₂ H₅or N, N-dimethylaminoethyl; R₂ is mono- or poly-substituted phenylwherein the substituents are alkyl(C₁ -C₆), alkoxy(C₁ -C₃), chloro,bromo, monoalkyl(C₁ -C₃)amino, dialkyl(C₁ -C₃)amino, alkyl(C₁ -C₃)keto,propenyloxy, carboxyl, oxyacetic acid, oxyacetic acid ethyl ester,sulfanilamido, N,N-dialkyl(C₁ -C₃)sulfanilamido, N-methylpiperazinyl,piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl,1-naphthyl, cyclopentyl, 3,4-dimethylbenzyl or moieties of the formulae:##STR8## wherein R is alkyl(C₁ -C₃), X is oxygen(--O--) orsulfur(--S--), m is 1-3, n is 2 or 3, R₆ is hydrogen, alkyl(C₁ -C₃),alkoxy(C₁ -C₃), chloro, bromo, iodo or trifluoromethyl, R₇ is1H-imidazol-1-yl or morpholino and R₈ is alkyl(C₁ -C₃), phenyl ormonosubstituted phenyl wherein the substituents are alkyl(C₁ -C₃),halogen or trifluoromethyl; R₃ is 2-pyridinyl, 3-pyridinyl,2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, 2-furanyl,5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl,5-methyl-2-thienyl, 2-phenothiazinyl, 4-pyrazinyl, 2-benzofuranyl,2-(pyridine-N-oxide), 3-(pyridine-N-oxide), 4-(pyridine-N-oxide),1H-indol-2-yl, 1H-indol-3-yl, 1-methyl-1H-pyrrol-2-yl, 4-quinolinyl,4-pyridinyl methyl iodide, dimethylaminophenyl orN-acteyl-N-methylaminophenyl; R₄ is hydrogen or alkyl(C₁ -C₃); andR.sub. 5 is hydrogen or alkyl(C₁ -C₃); and the pharmacologicallyacceptable acid-addition salts thereof.